Compositions having c-17 and c-3 modified triterpenoids with hiv maturation inhibitory activity

ABSTRACT

Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, C-17 and C-3 modified triterpenoids that possess unique antiviral activity are provided as HIV maturation inhibitors, as represented by compounds of Formulas I, II and III: 
     
       
         
         
             
             
         
       
     
     These compounds are useful for the treatment of HIV and AIDS.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. non-provisional applicationSer. No. 13/359,727 filed Jan. 27, 2012, now allowed, which claims thebenefit of U.S. provisional patent application No. 61/437,893 filed Jan.31, 2011, now expired, which is herein incorporated by reference in itsentirety.

FIELD OF THE INVENTION

The present invention relates to novel compounds useful against HIV and,more particularly, to compounds derived from betulinic acid and otherstructurally-related compounds which are useful as HIV maturationinhibitors, and to pharmaceutical compositions containing same, as wellas to methods for their preparation.

BACKGROUND OF THE INVENTION

HIV-1 (human immunodeficiency virus-1) infection remains a major medicalproblem, with an estimated 45-50 million people infected worldwide atthe end of 2010. The number of cases of HIV and AIDS (acquiredimmunodeficiency syndrome) has risen rapidly. In 2005, approximately 5.0million new infections were reported, and 3.1 million people died fromAIDS. Currently available drugs for the treatment of HIV includenucleoside reverse transcriptase (RT) inhibitors or approved single pillcombinations: zidovudine (or AZT or RETROVIR®), didanosine (or VIDEX®),stavudine (or ZERIT®), lamivudine (or 3TC or EPIVIR®), zalcitabine (orDDC or HIVID®), abacavir succinate (or ZIAGEN®), Tenofovir disoproxilfumarate salt (or VIREAD®), emtricitabine (or FTC—EMTRIVA®), COMBIVIR®(contains—3TC plus AZT), TRIZIVIR® (contains abacavir, lamivudine, andzidovudine), EPZICOM® (contains abacavir and lamivudine), TRUVADA®(contains VIREAD® and EMTRIVA®); non-nucleoside reverse transcriptaseinhibitors: nevirapine (or VIRAMUNE®, delavirdine (or RESCRIPTOR®) andefavirenz (or SUSTIVA®), ATRIPLA® (TRUVADA®+SUSTIVA®), and etravirine,and peptidomimetic protease inhibitors or approved formulations:saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir,KALETRA® (lopinavir and Ritonavir), darunavir, atazanavir (REYATAZ®) andtipranavir (APTIVUS®) and cobicistat, and integrase inhibitors such asraltegravir (ISENTRESS®), and entry inhibitors such as enfuvirtide(T-20) (FUZEON®) and maraviroc (SELZENTRY®).

Each of these drugs can only transiently restrain viral replication ifused alone. However, when used in combination, these drugs have aprofound effect on viremia and disease progression. In fact, significantreductions in death rates among AIDS patients have been recentlydocumented as a consequence of the widespread application of combinationtherapy. However, despite these impressive results, 30 to 50% ofpatients may ultimately fail combination drug therapies. Insufficientdrug potency, non-compliance, restricted tissue penetration anddrug-specific limitations within certain cell types (e.g. mostnucleoside analogs cannot be phosphorylated in resting cells) mayaccount for the incomplete suppression of sensitive viruses.Furthermore, the high replication rate and rapid turnover of HIV-1combined with the frequent incorporation of mutations, leads to theappearance of drug-resistant variants and treatment failures whensub-optimal drug concentrations are present. Therefore, novel anti-HIVagents exhibiting distinct resistance patterns, and favorablepharmacokinetic as well as safety profiles are needed to provide moretreatment options. Improved HIV fusion inhibitors and HIV entrycoreceptor antagonists are two examples of new classes of anti-HIVagents further being studied by a number of investigators.

HIV attachment inhibitors are a further subclass of antiviral compoundsthat bind to the HIV surface glycoprotein gp120, and interfere with theinteraction between the surface protein gp120 and the host cell receptorCD4. Thus, they prevent HIV from attaching to the human CD4 T-cell, andblock HIV replication in the first stage of the HIV life cycle. Theproperties of HIV attachment inhibitors have been improved in an effortto obtain compounds with maximized utility and efficacy as antiviralagents. In particular, U.S. Pat. No. 7,354,924 and US 2005/0209246 areillustrative of HIV attachment inhibitors.

Another emerging class of compounds for the treatment of HIV are calledHIV maturation inhibitors. Maturation is the last of as many as 10 ormore steps in HIV replication or the HIV life cycle, in which HIVbecomes infectious as a consequence of several HIV protease-mediatedcleavage events in the gag protein that ultimately results in release ofthe capsid (CA) protein. Maturation inhibitors prevent the HIV capsidfrom properly assembling and maturing, from forming a protective outercoat, or from emerging from human cells. Instead, non-infectious virusesare produced, preventing subsequent cycles of HIV infection.

Certain derivatives of betulinic acid have now been shown to exhibitpotent anti-HIV activity as HIV maturation inhibitors. For example, U.S.Pat. No. 7,365,221 discloses monoacylated betulin and dihydrobetulinederivatives, and their use as anti-HIV agents. As discussed in the '221reference, esterification of betulinic acid (1) with certain substitutedacyl groups, such as 3′,3′-dimethylglutaryl and 3′,3′-dimethylsuccinylgroups produced derivatives having enhanced activity (Kashiwada, Y., etal., J. Med. Chem. 39:1016-1017 (1996)). Acylated betulinic acid anddihydrobetulinic acid derivatives that are potent anti-HIV agents arealso described in U.S. Pat. No. 5,679,828. Esterification of thehydroxyl in the 3 carbon of betulin with succinic acid also produced acompound capable of inhibiting HIV-1 activity (Pokrovskii, A. G. et al.,“Synthesis of derivatives of plant triterpenes and study of theirantiviral and immunostimulating activity”, Khimiya y InteresakhUstoichivogo Razvitiya, Vol. 9, No. 3, pp. 485-491 (2001) (Englishabstract)).

Other references to the use of treating HIV infection with compoundsderived from betulinic acid include US 2005/0239748 and US 2008/0207573,as well as WO2006/053255, WO2009/100532 and WO2011/007230.

One HIV maturation compound that has been in development has beenidentified as Bevirimat or PA-457, with the chemical formula of C₃₆H₅₆O₆and the IUPAC name of 3β-(3-carboxy-3-methyl-butanoyloxy)lup-20(29)-en-28-oic acid.

Reference is also made herein to the applications by Bristol-MyersSquibb entitled “MODIFIED C-3 BETULINIC ACID DERIVATIVES AS HIVMATURATION INHIBITORS” U.S. Ser. No. 13/151,706 filed on Jun. 2, 2011(now US 2012-0142707) and “C-28 AMIDES OF MODIFIED C-3 BETULINIC ACIDDERIVATIVES AS HIV MATURATION INHIBITORS” U.S. Ser. No. 13/151,722,filed on Jun. 2, 2011 (now US 2012-0142653). Reference is also made tothe application entitled “C-28 AMINES OF C-3 MODIFIED BETULINIC ACIDDERIVATIVES AS HIV MATURATION INHIBITORS” U.S. Ser. No. 61/437,870,filed on Jan. 31, 2011 (now U.S. Pat. No. 8,748,415).

What is now needed in the art are new compounds which are useful as HIVmaturation inhibitors, as well as new pharmaceutical compositionscontaining these compounds.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formulas I, II, and IIIbelow, including pharmaceutically acceptable salts thereof, theirpharmaceutical formulations, and their use in patients suffering from orsusceptible to a virus such as HIV. The compounds of Formulas I-III areeffective antiviral agents, particularly as inhibitors of HIV. They areuseful for the treatment of HIV and AIDS.

One embodiment of the present invention is directed to a compound,including pharmaceutically acceptable salts thereof, which is selectedfrom the group of:

a compound of formula I

a compound of formula II

anda compound of formula III

wherein R₁ is isopropenyl or isopropyl;J and E are independently —H or —CH₃, and E is absent when the doublebond is present;X is a phenyl or heteroaryl ring substituted with A, wherein A is atleast one member selected from the group of —H, -halo, -hydroxyl, —C₁₋₆alkyl, —C₁₋₆ alkoxy, and —COOR₂;R₂ is —H, —C₁₋₆ alkyl, -alkyl substituted C₁₋₆ alkyl or -arylsubstituted C₁₋₆ alkyl;Y is selected from the group of —COOR₂, —C(O)NR₂SO₂R₃, —C(O)NHSO₂NR₂R₂,—NR₂SO₂R₂, —SO₂NR₂R₂, —C₃₋₆ cycloalkyl-COOR₂, —C₂₋₆ alkenyl-COOR₂, —C₂₋₆alkynyl-COOR₂, —C₁₋₆alkyl-COOR₂, —NHC(O)(CH₂)_(n)—COOR₂, —SO₂NR₂C(O)R₂,-tetrazole, and —CONHOH,wherein n=1-6;R₃ is —C₁₋₆ alkyl or -alkyl substituted C₁₋₆ alkyl;R₄ is selected from the group of —H, —C₁₋₆ alkyl,—C₁₋₆alkyl-C(OR₃)₂—C₃₋₆cycloalkyl, —C₁₋₆ substituted alkyl,—C₁₋₆alkyl-C₃₋₆cycloalkyl, —C₁₋₆ alkyl-Q₁, —C₁₋₆ alkyl-C₃₋₆cycloalkyl-Q₁, aryl, heteroaryl, substituted heteroaryl, —COR₆, —COCOR₆,—SO₂R₇, —SO₂NR₂R₂,

wherein Q₁ is selected from the group of heteroaryl, substitutedheteroaryl, halogen, —CF₃, —OR₂, —COOR₂, —NR₈R₉, —CONR₁₀R₁₁ and —SO₂R₇;R₅ is selected from the group of —H, —C₁₋₆ alkyl, —C₃₋₆ cycloalkyl,—C₁₋₆ alkyl substituted alkyl, —C₁₋₆alkyl-NR₈R₉, —COR₁₀, —COR₆, —COCOR₆,—SO₂R₇ and —SO₂NR₂R₂;with the proviso that only one of R₄ or R₅ can be selected from thegroup of —COR₆, —COCOR₆, —SO₂R₇ and —SO₂NR₂R₂;or R₄ and R₅ are taken together with the adjacent N to form

R₆ is selected from the group of —H, —C₁₋₆ alkyl, —C₁₋₆alkyl-substituted alkyl, —C₃₋₆ cycloalkyl, —C₃₋₆ substitutedcycloalkyl-Q₂, —C₁₋₆ alkyl-Q₂, —C₁₋₆ alkyl-substituted alkyl-Q₂, —C₃₋₆cycloalkyl-Q₂, aryl-Q₂, —NR₁₃R₁₄, and —OR₁₅;wherein Q₂ is selected from the group of aryl, heteroaryl, substitutedheteroaryl, —OR₂, —COOR₂, —NR₈R₉, SO₂R₇, —CONHSO₂R₃, and —CONHSO₂NR₂R₂;R₂ is selected from the group of —C₁₋₆ alkyl, —C₁₋₆ substituted alkyl,—C₃₋₆ cycloalkyl, aryl, and heteroaryl;R₈ and R₉ are independently selected from the group of —H, —C₁₋₆ alkyl,—C₁₋₆ substituted alkyl, aryl, heteroaryl, substituted aryl, substitutedheteroaryl, —C₁₋₆ alkyl-Q₂, and —COOR₃,and R₈ and R₉ can also be independently selected from the group of

or R₈ and R₉ are taken together with the adjacent N to form a cycleselected from the group of:

with the proviso that only one of R₈ or R₉ can be —COOR₃;R₁₀ and R₁₁ are independently selected from the group of —H, —C₁₋₆alkyl, —C₁₋₆ substituted alkyl and —C₃₋₆ cycloalkyl,or R₁₀ and R₁₁ are taken together with the adjacent N to form a cyclesuch as

R₁₂ is selected from the group of —C₁₋₆ alkyl, —C₁₋₆ alkyl-OH; —C₁₋₆alkyl, —C₁₋₆ substituted alkyl, —C₃₋₆ cycloalkyl, —COR₇, —COONR₂₂R₂₃,—SOR₇, and —SONR₂₄R₂₅;R₁₃ and R₁₄ are independently selected from the group of —H, —C₁₋₆alkyl, —C₃₋₆ cycloalkyl, —C₁₋₆ substituted alkyl, —C₁₋₆ alkyl-Q₃, —C₁₋₆alkyl-C₃₋₆ cycloalkyl-Q₃, C₁₋₆ substituted alkyl-Q₃ and

or R₁₃ and R₁₄ are taken together with the adjacent N to form a cycleselected from the group of:

Q₃ is selected from the group of heteroaryl, substituted heteroaryl,—NR₂₀R₂₁, ⁻CONR₂R₂, —COOR₂, —OR₂, and —SO₂R₃;R₁₅ is selected from the group of —C₁₋₆ alkyl, —C₃₋₆ cycloalkyl, —C₁₋₆substituted alkyl, —C₁₋₆ alkyl-Q₃, —C₁₋₆alkyl-C₃₋₆cycloalkyl-Q₃ and—C₁₋₆ substituted alkyl-Q₃,R₁₆ is selected from the group of —H, —C₁₋₆ alkyl, —NR₂R₂, and —COOR₃;R₁₇ is selected from the group of —H, —C₁₋₆ alkyl, —COOR₃, and aryl;R₁₈ is selected from the group of —COOR₂ and —C₁₋₆ alkyl-COOR₂;R₁₉ is selected from the group of —H, —C₁₋₆ alkyl, —C₁₋₆ alkyl-Q₄,—COR₃, —COOR₃, wherein Q₄ is selected from the group of —NR₂R₂ and —OR₂;R₂₀ and R₂₁ are independently selected from the group of —H, —C₁₋₆alkyl, —C₁₋₆ substituted alkyl, —C₁₋₆ substituted alkyl-OR₂, and —COR₃,or R₂₀ and R₂₁ are taken together with the adjacent N to form a cycleselected from the group of

with the proviso that only one of R₂₀ or R₂₁ can be —COR₃,R₂₂ and R₂₃ are independently selected from the group of H, —C₁₋₆ alkyl,—C₁₋₆ substituted alkyl, and —C₁₋₆cycloalkyl,or R₂₂ and R₂₃ are taken together with the adjacent N to form a cycleselected from the group of

R₂₄ and R₂₅ are independently from the group of H, —C₁₋₆ alkyl, —C₁₋₆substituted alkyl, —C₁₋₆ alkyl-Q₅, —Cl_(—)6 cycloalkyl, aryl,substituted aryl, heteroaryl, and substituted heteroaryl,and Q₅ is selected from the group of halogen and SO₂R₃.

In a further embodiment, there is provided a method for treating mammalsinfected with a virus, especially wherein said virus is HIV, comprisingadministering to said mammal an antiviral effective amount of a compoundwhich is selected from the group of compounds of Formulas I, II, IIIabove, and one or more pharmaceutically acceptable carriers, excipientsor diluents. Optionally, the compound of Formulas I, II, and/or III canbe administered in combination with an antiviral effective amount ofanother-AIDS treatment agent selected from the group consisting of: (a)an AIDS antiviral agent; (b) an anti-infective agent; (c) animmunomodulator; and (d) other HIV entry inhibitors.

Another embodiment of the present invention is a pharmaceuticalcomposition comprising an antiviral effective amount of a compound whichis selected from the group of compounds of Formulas I, II, and III, andone or more pharmaceutically acceptable carriers, excipients, anddiluents; and optionally in combination with an antiviral effectiveamount of another AIDS treatment agent selected from the groupconsisting of: (a) an AIDS antiviral agent; (b) an anti-infective agent;(c) an immunomodulator; and (d) other HIV entry inhibitors.

In another embodiment of the invention there is provided one or moremethods for making the compounds of Formulas I, II, and III herein.

Also provided herein are intermediate compounds useful in making thecompounds of Formulas I, II, and III herein.

The present invention is directed to these, as well as other importantends, hereinafter described.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Since the compounds of the present invention may possess asymmetriccenters and therefore occur as mixtures of diastereomers andenantiomers, the present disclosure includes the individualdiastereoisomeric and enantiomeric forms of the compounds of Formulas I,II and III in addition to the mixtures thereof.

DEFINITIONS

Unless otherwise specifically set forth elsewhere in the application,one or more of the following terms may be used herein, and shall havethe following meanings:

“H” refers to hydrogen, including its isotopes, such as deuterium.

The term “C₁₋₆ alkyl” as used herein and in the claims (unless specifiedotherwise) mean straight or branched chain alkyl groups such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and thelike.

“C₁-C₄ fluoroalkyl” refers to F-substituted C₁-C₄ alkyl wherein at leastone H atom is substituted with F atom, and each H atom can beindependently substituted by F atom;

“Halogen” refers to chlorine, bromine, iodine or fluorine.

An “aryl” or “Ar” group refers to an all carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. Examples,without limitation, of aryl groups are phenyl, napthalenyl andanthracenyl. The aryl group may be substituted or unsubstituted. Whensubstituted the substituted group(s) is preferably one or more selectedfrom alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy,thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen,nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, aminoand —NR^(x)R^(y), wherein R^(x) and R^(y) are independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl, aryl,carbonyl, C-carboxy, sulfonyl, trihalomethyl, and, combined, a five- orsix-member heteroalicyclic ring.

As used herein, a “heteroaryl” group refers to a monocyclic or fusedring (i.e., rings which share an adjacent pair of atoms) group having inthe ring(s) one or more atoms selected from the group consisting ofnitrogen, oxygen and sulfur and, in addition, having a completelyconjugated pi-electron system. Unless otherwise indicated, theheteroaryl group may be attached at either a carbon or nitrogen atomwithin the heteroaryl group. It should be noted that the term heteroarylis intended to encompass an N-oxide of the parent heteroaryl if such anN-oxide is chemically feasible as is known in the art. Examples, withoutlimitation, of heteroaryl groups are furyl, thienyl, benzothienyl,thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl,quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzoxazolyl,benzimidazolyl, indolyl, isoindolyl, pyrazinyl. diazinyl, pyrazine,triazinyl, tetrazinyl, and tetrazolyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thioalkoxy, thiohydroxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido,amino, and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

As used herein, a “heteroalicyclic” group refers to a monocyclic orfused ring group having in the ring(s) one or more atoms selected fromthe group consisting of nitrogen, oxygen and sulfur. Rings are selectedfrom those which provide stable arrangements of bonds and are notintended to encompass systems which would not exist. The rings may alsohave one or more double bonds. However, the rings do not have acompletely conjugated pi-electron system. Examples, without limitation,of heteroalicyclic groups are azetidinyl, piperidyl, piperazinyl,imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl,thiomorpholinyl and tetrahydropyranyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy,sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido,trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido, phosphonyl,amino and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

An “alkyl” group refers to a saturated aliphatic hydrocarbon includingstraight chain and branched chain groups. Preferably, the alkyl grouphas 1 to 20 carbon atoms (whenever a numerical range; e.g., “1-20”, isstated herein, it means that the group, in this case the alkyl group maycontain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to andincluding 20 carbon atoms). More preferably, it is a medium size alkylhaving 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having1 to 4 carbon atoms. The alkyl group may be substituted orunsubstituted. When substituted, the substituent group(s) is preferablyone or more individually selected from trihaloalkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy,heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, andcombined, a five- or six-member heteroalicyclic ring.

A “cycloalkyl” group refers to an all-carbon monocyclic or fused ring(i.e., rings which share and adjacent pair of carbon atoms) groupwherein one or more rings does not have a completely conjugatedpi-electron system. Examples, without limitation, of cycloalkyl groupsare cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,cyclohexene, cycloheptane, cycloheptene and adamantane. A cycloalkylgroup may be substituted or unsubstituted. When substituted, thesubstituent group(s) is preferably one or more individually selectedfrom alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalo-methanesulfonamido, trihalomethanesulfonyl, silyl,amidino, guanidino, ureido, phosphonyl, amino and —NR^(x)R^(y) withR^(x) and R^(y) as defined above.

An “alkenyl” group refers to an alkyl group, as defined herein, havingat least two carbon atoms and at least one carbon-carbon double bond.

An “alkynyl” group refers to an alkyl group, as defined herein, havingat least two carbon atoms and at least one carbon-carbon triple bond.

A “hydroxy” group refers to an —OH group.

An “alkoxy” group refers to both an —O-alkyl and an —O-cycloalkyl groupas defined herein.

An “aryloxy” group refers to both an —O-aryl and an —O-heteroaryl group,as defined herein.

A “heteroaryloxy” group refers to a heteroaryl-O— group with heteroarylas defined herein.

A “heteroalicycloxy” group refers to a heteroalicyclic-O— group withheteroalicyclic as defined herein.

A “thiohydroxy” group refers to an —SH group.

A “thioalkoxy” group refers to both an S-alkyl and an —S-cycloalkylgroup, as defined herein.

A “thioaryloxy” group refers to both an —S-aryl and an —S-heteroarylgroup, as defined herein.

A “thioheteroaryloxy” group refers to a heteroaryl-S— group withheteroaryl as defined herein.

A “thioheteroalicycloxy” group refers to a heteroalicyclic-S— group withheteroalicyclic as defined herein.

A “carbonyl” group refers to a —C(═O)—R″ group, where R″ is selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon), as each is definedherein.

An “aldehyde” group refers to a carbonyl group where R″ is hydrogen.

A “thiocarbonyl” group refers to a —C(═S)—R″ group, with R″ as definedherein.

A “Keto” group refers to a —CC(═O)C— group wherein the carbon on eitheror both sides of the C═O may be alkyl, cycloalkyl, aryl or a carbon of aheteroaryl or heteroalicyclic group.

A “trihalomethanecarbonyl” group refers to a Z₃CC(═O)— group with said Zbeing a halogen.

A “C-carboxy” group refers to a —C(═O)O—R″ groups, with R″ as definedherein.

An “O-carboxy” group refers to a R″C(—O)O-group, with R″ as definedherein.

A “carboxylic acid” group refers to a C-carboxy group in which R″ ishydrogen.

A “trihalomethyl” group refers to a —CZ₃, group wherein Z is a halogengroup as defined herein.

A “trihalomethanesulfonyl” group refers to an Z₃CS(═O)₂— groups with Zas defined above.

A “trihalomethanesulfonamido” group refers to a Z₃CS(═O)₂NR^(x)— groupwith Z as defined above and Rx being H or (C₁₋₆)alkyl.

A “sulfinyl” group refers to a —S(═O)—R″ group, with R″ being(C₁₋₆)alkyl.

A “sulfonyl” group refers to a —S(═O)₂R″ group with R″ being(C₁₋₆)alkyl.

A “S-sulfonamido” group refers to a —S(═O)₂NR^(X)R^(Y), with R^(X) andR_(Y) independently being H or (C₁₋₆)alkyl.

A “N-Sulfonamido” group refers to a R″S(═O)₂NR_(X)— group, with R_(x)being H or (C₁₋₆)alkyl.

A “O-carbamyl” group refers to a —OC(═O)NR^(x)R^(y) group, with R^(X)and R^(Y) independently being H or (C₁₋₆)alkyl.

A “N-carbamyl” group refers to a R^(x)OC(═O)NR^(y) group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “O-thiocarbamyl” group refers to a —OC(═S)NR^(x)R^(y) group, withR^(x) and R^(y) independently being H or (C₁₋₆)alkyl.

A “N-thiocarbamyl” group refers to a R^(x)OC(═S)NR^(y)— group, withR^(x) and R^(Y) independently being H or (C₁₋₆)alkyl.

An “amino” group refers to an —NH₂ group.

A “C-amido” group refers to a —C(═O)NR^(x)R^(y) group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “C-thioamido” group refers to a —C(═S)NR^(x)R^(y) group, with R^(x)and R^(y) independently being H or (C₁₋₆)alkyl.

A “N-amido” group refers to a R^(x)(═O)NR^(y)— group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

An “ureido” group refers to a —NR^(x)C(═O)NR^(y)R^(y2) group, withR^(x), R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “guanidino” group refers to a —R^(x)NC(═N)NR^(y)R^(y2) group, withR^(x), R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “amidino” group refers to a R^(x)R^(y)NC(═N)— group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “cyano” group refers to a —CN group.

A “silyl” group refers to a —Si(R″)₃, with R″ being (C₁₋₆)alkyl orphenyl.

A “phosphonyl” group refers to a P(═O)(OR^(x))₂ with R^(x) being(C₁₋₆)alkyl.

A “hydrazino” group refers to a —NR^(x)NR^(y)R^(y2) group, with R^(x),R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “4, 5, or 6 membered ring cyclic N-lactam” group refers to

Any two adjacent R groups may combine to form an additional aryl,cycloalkyl, heteroaryl or heterocyclic ring fused to the ring initiallybearing those R groups.

It is known in the art that nitrogen atoms in heteroaryl systems can be“participating in a heteroaryl ring double bond”, and this refers to theform of double bonds in the two tautomeric structures which comprisefive-member ring heteroaryl groups. This dictates whether nitrogens canbe substituted as well understood by chemists in the art. The disclosureand claims of the present disclosure are based on the known generalprinciples of chemical bonding. It is understood that the claims do notencompass structures known to be unstable or not able to exist based onthe literature.

Pharmaceutically acceptable salts and prodrugs of compounds disclosedherein are within the scope of the invention. The term “pharmaceuticallyacceptable salt” as used herein and in the claims is intended to includenontoxic base addition salts. Suitable salts include those derived fromorganic and inorganic acids such as, without limitation, hydrochloricacid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonicacid, acetic acid, tartaric acid, lactic acid, sulfinic acid, citricacid, maleic acid, fumaric acid, sorbic acid, aconitic acid, salicylicacid, phthalic acid, and the like. The term “pharmaceutically acceptablesalt” as used herein is also intended to include salts of acidic groups,such as a carboxylate, with such counterions as ammonium, alkali metalsalts, particularly sodium or potassium, alkaline earth metal salts,particularly calcium or magnesium, and salts with suitable organic basessuch as lower alkylamines (methylamine, ethylamine, cyclohexylamine, andthe like) or with substituted lower alkylamines (e.g.hydroxyl-substituted alkylamines such as diethanolamine, triethanolamineor tris(hydroxymethyl)-aminomethane), or with bases such as piperidineor morpholine.

As stated above, the compounds of the invention also include “prodrugs”.The term “prodrug” as used herein encompasses both the term “prodrugesters” and the term “prodrug ethers”. The term “prodrug esters” asemployed herein includes esters and carbonates formed by reacting one ormore hydroxyls of compounds of Formula I with either alkyl, alkoxy, oraryl substituted acylating agents or phosphorylating agent employingprocedures known to those skilled in the art to generate acetates,pivalates, methylcarbonates, benzoates, amino acid esters, phosphates,half acid esters such as malonates, succinates or glutarates, and thelike. In certain embodiments, amino acid esters may be especiallypreferred.

Examples of such prodrug esters include

The term “prodrug ethers” include both phosphate acetals andO-glucosides. Representative examples of such prodrug ethers include

As set forth above, the invention is directed to a compound, includingpharmaceutically acceptable salts thereof, which is selected from thegroup of:

a compound of formula I

a compound of formula II

anda compound of formula III

wherein R₁ is isopropenyl or isopropyl;J and E are independently —H or —CH₃, and E is absent when the doublebond is present;X is a phenyl or heteroaryl ring substituted with A, wherein A is atleast one member selected from the group of —H, -halo, -hydroxyl, —C₁₋₆alkyl, —C₁₋₆ alkoxy, and —COOR₂;R₂ is —H, —C₁₋₆ alkyl, -alkyl substituted C₁₋₆alkyl or -aryl substitutedC₁₋₆ alkyl;Y is selected from the group of —COOR₂, —C(O)NR₂SO₂R₃, —C(O)NHSO₂NR₂R₂,—NR₂SO₂R₂, —SO₂NR₂R₂, —C₃₋₆ cycloalkyl-COOR₂, —C₂₋₆ alkenyl-COOR₂, —C₂₋₆alkynyl-COOR₂, —C₁₋₆alkyl-COOR₂, —NHC(O)(CH₂)_(n)—COOR₂, —SO₂NR₂C(O)R₂,-tetrazole, and —CONHOH,wherein n=1-6;R₃ is —C₁₋₆ alkyl or -alkyl substituted C₁₋₆ alkyl;R₄ is selected from the group of —H, —C₁₋₆ alkyl,—C₁₋₆alkyl-C(OR₃)₂—C₃₋₆cycloalkyl, —C₁₋₆ substituted alkyl,—C₁₋₆alkyl-C₃₋₆cycloalkyl, —C₁₋₆ alkyl-Q₁, —C₁₋₆ alkyl-C₃₋₆cycloalkyl-Q₁, aryl, heteroaryl, substituted heteroaryl, —COR₆, —COCOR₆,—SO₂R₇, —SO₂NR₂R₂,

wherein Q₁ is selected from the group of heteroaryl, substitutedheteroaryl, halogen, —CF₃, —OR₂, —COOR₂, —NR₈R₉, —CONR₁₀R₁₁ and —SO₂R₇;R₅ is selected from the group of —H, —C₁₋₆ alkyl, —C₃₋₆ cycloalkyl,—C₁₋₆ alkyl substituted alkyl, —C₁₋₆alkyl-NR₈R₉, —COR₁₀, —COR₆, —COCOR₆,—SO₂R₇ and —SO₂NR₂R₂;with the proviso that only one of R₄ or R₅ can be selected from thegroup of —COR₆, —COCOR₆, —SO₂R₇ and —SO₂NR₂R₂;or R₄ and R₅ are taken together with the adjacent N to form

R₆ is selected from the group of —H, —C₁₋₆ alkyl, —C₁₋₆alkyl-substituted alkyl, —C₃₋₆ cycloalkyl, —C₃₋₆ substitutedcycloalkyl-Q₂, —C₁₋₆ alkyl-Q₂, —C₁₋₆ alkyl-substituted alkyl-Q₂, —C₃₋₆cycloalkyl-Q₂, aryl-Q₂, —NR₁₃R₁₄, and —OR₁₅;wherein Q₂ is selected from the group of aryl, heteroaryl, substitutedheteroaryl, —OR₂, —COOR₂, —NR₈R₉, SO₂R₇, —CONHSO₂R₃, and —CONHSO₂NR₂R₂;R₇ is selected from the group of —C₁₋₆ alkyl, —C₁₋₆ substituted alkyl,—C₃₋₆ cycloalkyl, aryl, and heteroaryl;R₈ and R₉ are independently selected from the group of —H, —C₁₋₆ alkyl,—C₁₋₆ substituted alkyl, aryl, heteroaryl, substituted aryl, substitutedheteroaryl, —C₁₋₆ alkyl-Q₂, and —COOR₃,and R₈ and R₉ can also be independently selected from the group of

or R₈ and R₉ are taken together with the adjacent N to form a cycleselected from the group of:

with the proviso that only one of R₈ or R₉ can be —COOR₃;R₁₀ and R₁₁ are independently selected from the group of —H, —C₁₋₆alkyl, —C₁₋₆ substituted alkyl and —C₃₋₆ cycloalkyl,or R₁₀ and R₁₁ are taken together with the adjacent N to form a cyclesuch as

R₁₂ is selected from the group of —C₁₋₆ alkyl, —C₁₋₆ alkyl-OH, —C₁₋₆alkyl, —C₁₋₆ substituted alkyl, —C₃₋₆ cycloalkyl, —COR₇, —COONR₂₂R₂₃,—SOR₇, and —SONR₂₄R₂₅;R₁₃ and R₁₄ are independently selected from the group of —H, —C₁₋₆alkyl, —C₃₋₆ cycloalkyl, —C₁₋₆ substituted alkyl, —C₁₋₆ alkyl-Q₃,alkyl-C₃₋₆ cycloalkyl-Q₃, C₁₋₆ substituted alkyl-Q₃ and

or R₁₃ and R₁₄ are taken together with the adjacent N to form a cycleselected from the group of:

Q₃ is selected from the group of heteroaryl, substituted heteroaryl,—NR₂OR₂₁, —CONR₂R₂, —COOR₂, —OR₂, and —SO₂R₃;R₁₅ is selected from the group of —C₁₋₆ alkyl, —C₃₋₆ cycloalkyl, —C₁₋₆substituted alkyl, —C₁₋₆ alkyl-Q₃, —C₁₋₆ alkyl-C₃₋₆ cycloalkyl-Q₃ and—C₁₋₆ substituted alkyl-Q₃,R₁₆ is selected from the group of —H, —C₁₋₆ alkyl, —NR₂R₂, and —COOR₃;R₁₇ is selected from the group of —H, —C₁₋₆ alkyl, —COOR₃, and aryl;R₁₈ is selected from the group of —COOR₂ and —C₁₋₆ alkyl-COOR₂;R₁₉ is selected from the group of —H, —C₁₋₆ alkyl, —C₁₋₆ alkyl-Q₄,—COR₃, —COOR₃, wherein Q₄ is selected from the group of —NR₂R₂ and —OR₂;R₂₀ and R₂₁ are independently selected from the group of —H, —C₁₋₆alkyl, —C₁₋₆ substituted alkyl, —C₁₋₆ substituted alkyl-OR₂, and —COR₃,or R₂₀ and R₂₁ are taken together with the adjacent N to form a cycleselected from the group of

with the proviso that only one of R₂₀ or R₂₁ can be —COR₃,R₂₂ and R₂₃ are independently selected from the group of H, —C₁₋₆ alkyl,—C₁₋₆ substituted alkyl, and —C₁₋₆cycloalkyl,or R₂₂ and R₂₃ are taken together with the adjacent N to form a cycleselected from the group of

R₂₄ and R₂₅ are independently from the group of H, —C₁₋₆ alkyl, —C₁₋₆substituted alkyl, —C₁₋₆ alkyl-Q₅, —C₁₋₆cycloalkyl, aryl, substitutedaryl, heteroaryl, and substituted heteroaryl,and Q₅ is selected from the group of halogen and SO₂R₃.

Even more preferred compounds include those wherein R₁ is isopropenyl.

More preferred compounds include those which are encompassed by FormulaI. Of these, those wherein X is a phenyl ring are even more preferred.Even more preferred are compounds of Formula I wherein X is a phenylring and Y is in the para position.

Also preferred are compounds of Formula I wherein A is at least onemember selected from the group of —H, —OH, -halo, —C₁₋₃alkyl, and—C₁₋₃alkoxy, wherein -halo is selected from the group of —Cl, —F and—Br, with —F being more preferred. It is even more preferred that A is—H.

Also preferred are compounds of Formula I wherein Y is —COOR₂, and morepreferably —COOH.

Also preferred are compounds wherein R₄ is selected from the group of—H, —C₁₋₆ alkyl, —C₁₋₆ alkyl-Q₁, and —COR₆. Especially preferred arecompounds wherein R₄ is —C₁₋₆ alkyl-Q₁ or —COR₆.

It is also preferred that R₅ is —H.

In addition, it is preferred that Q₁ is —NR₈R₉.

In another preferred embodiment there is provided a compound of FormulaIa below wherein X is a phenyl ring and Y is —COOH in the para position:

In this embodiment, it is also preferred that A is at least one memberselected from the group of —H, -halo, —OH, —C₁₋₃alkyl and —C₁₋₃alkoxy.It is particularly preferred that A is at least one member selected fromthe group of —H, -fluoro, -chloro, —OH, -methyl and -methoxy, with —Hbeing even more preferred.

In addition, in a further embodiment of the invention compounds ofFormula II are preferred, as are compounds of Formula III.

Other compounds, including pharmaceutically acceptable salts thereof,which are preferred as part of the invention include the following:

Also preferred are the following compounds, including pharmaceuticallyacceptable salts thereof:

The compounds of the present invention, according to all the variousembodiments described above, may be administered orally, parenterally(including subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques), by inhalation spray, orrectally, and by other means, in dosage unit formulations containingnon-toxic pharmaceutically acceptable carriers, excipients and diluentsavailable to the skilled artisan. One or more adjuvants may also beincluded.

Thus, in accordance with the present invention, there is furtherprovided a method of treatment, and a pharmaceutical composition, fortreating viral infections such as HIV infection and AIDS. The treatmentinvolves administering to a patient in need of such treatment apharmaceutical composition which contains an antiviral effective amountof one or more of the compounds of Formulas I, II, and/or III, togetherwith one or more pharmaceutically acceptable carriers, excipients ordiluents. As used herein, the term “antiviral effective amount” meansthe total amount of each active component of the composition and methodthat is sufficient to show a meaningful patient benefit, i.e.,inhibiting, ameliorating, or healing of acute conditions characterizedby inhibition of the HIV infection. When applied to an individual activeingredient, administered alone, the term refers to that ingredientalone. When applied to a combination, the term refers to combinedamounts of the active ingredients that result in the therapeutic effect,whether administered in combination, serially or simultaneously. Theterms “treat, treating, treatment” as used herein and in the claimsmeans preventing, ameliorating or healing diseases associated with HIVinfection.

The pharmaceutical compositions of the invention may be in the form oforally administrable suspensions or tablets; as well as nasal sprays,sterile injectable preparations, for example, as sterile injectableaqueous or oleaginous suspensions or suppositories. Pharmaceuticallyacceptable carriers, excipients or diluents may be utilized in thepharmaceutical compositions, and are those utilized in the art ofpharmaceutical preparations.

When administered orally as a suspension, these compositions areprepared according to techniques typically known in the art ofpharmaceutical formulation and may contain microcrystalline cellulosefor imparting bulk, alginic acid or sodium alginate as a suspendingagent, methylcellulose as a viscosity enhancer, and sweeteners/flavoringagents known in the art. As immediate release tablets, thesecompositions may contain microcrystalline cellulose, dicalciumphosphate, starch, magnesium stearate and lactose and/or otherexcipients, binders, extenders, disintegrants, diluents, and lubricantsknown in the art.

The injectable solutions or suspensions may be formulated according toknown art, using suitable non-toxic, parenterally acceptable diluents orsolvents, such as mannitol, 1,3-butanediol, water, Ringer's solution orisotonic sodium chloride solution, or suitable dispersing or wetting andsuspending agents, such as sterile, bland, fixed oils, includingsynthetic mono- or diglycerides, and fatty acids, including oleic acid.

The compounds herein set forth can be administered orally to humans in adosage range of about 1 to 100 mg/kg body weight in divided doses,usually over an extended period, such as days, weeks, months, or evenyears. One preferred dosage range is about 1 to 10 mg/kg body weightorally in divided doses. Another preferred dosage range is about 1 to 20mg/kg body weight in divided doses. It will be understood, however, thatthe specific dose level and frequency of dosage for any particularpatient may be varied and will depend upon a variety of factorsincluding the activity of the specific compound employed, the metabolicstability and length of action of that compound, the age, body weight,general health, sex, diet, mode and time of administration, rate ofexcretion, drug combination, the severity of the particular condition,and the host undergoing therapy.

Also contemplated herein are combinations of the compounds of FormulasI, II, and/or III herein set forth, together with one or more otheragents useful in the treatment of AIDS. For example, the compounds ofthis disclosure may be effectively administered, whether at periods ofpre-exposure and/or post-exposure, in combination with effective amountsof the AIDS antivirals, immunomodulators, antiinfectives, or vaccines,such as those in the following non-limiting table:

ANTIVIRALS Drug Name Manufacturer Indication 097 Hoechst/Bayer HIVinfection, AIDS, ARC (non-nucleoside reverse transcriptase (RT)inhibitor) Amprenavir Glaxo Wellcome HIV infection, 141 W94 AIDS, ARC GW141 (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome HIVinfection, GW 1592 AIDS, ARC (RT inhibitor) Acemannan Carrington LabsARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARCAD-439 Tanox Biosystems HIV infection, AIDS, ARC AD-519 Tanox BiosystemsHIV infection, AIDS, ARC Adefovir dipivoxil Gilead Sciences HIVinfection AL-721 Ethigen ARC, PGL (Los Angeles, CA) HIV positive, AIDSAlpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV in combinationw/Retrovir Ansamycin Adria Laboratories ARC LM 427 (Dublin, OH) Erbamont(Stamford, CT) Antibody which Advanced Biotherapy AIDS, ARC NeutralizespH Concepts Labile alpha aberrant (Rockville, MD) Interferon AR177Aronex Pharm HIV infection, AIDS, ARC Beta-fluoro-ddA Nat'l CancerInstitute AIDS-associated diseases BMS-234475 Bristol-Myers Squibb/ HIVinfection, (CGP-61755) Novartis AIDS, ARC (protease inhibitor) CI-1012Warner-Lambert HIV-1 infection Cidofovir Gilead Science CMV retinitis,herpes, papillomavirus Curdlan sulfate AJI Pharma USA HIV infectionCytomegalovirus MedImmune CMV retinitis Immune globin Cytovene SyntexSight threatening Ganciclovir CMV peripheral CMV retinitis DarunavirTibotec-J & J HIV infection, AIDS, ARC (protease inhibitor) DelaviridinePharmacia-Upjohn HIV infection, AIDS, ARC (RT inhibitor) Dextran SulfateUeno Fine Chem. AIDS, ARC, HIV Ind. Ltd. (Osaka, positive Japan)asymptomatic ddC Hoffman-La Roche HIV infection, AIDS, DideoxycytidineARC ddI Bristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC;combination with AZT/d4T DMP-450 AVID HIV infection, (Camden, NJ) AIDS,ARC (protease inhibitor) Efavirenz Bristol Myers Squibb HIV infection,(DMP 266, SUSTIVA ®) AIDS, ARC (−)6-Chloro-4-(S)- (non-nucleoside RTcyclopropylethynyl- inhibitor) 4(S)-trifluoro- methyl-1,4-dihydro-2H-3,1-benzoxazin- 2-one, STOCRINE EL10 Elan Corp, PLC HIV infection(Gainesville, GA) Etravirine Tibotec/J & J HIV infection, AIDS, ARC(non-nucleoside reverse transcriptase inhibitor) Famciclovir Smith Klineherpes zoster, herpes simplex GS 840 Gilead HIV infection, AIDS, ARC(reverse transcriptase inhibitor) HBY097 Hoechst Marion HIV infection,Roussel AIDS, ARC (non-nucleoside reverse transcriptase inhibitor)Hypericin VIMRx Pharm. HIV infection, AIDS, ARC Recombinant Human TritonBiosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARCInterferon alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIVinfection, AIDS, ARC, asymptomatic HIV positive, also in combinationwith AZT/ddI/ddC ISIS 2922 ISIS Pharmaceuticals CMV retinitis KNI-272Nat'l Cancer Institute HIV-assoc. diseases Lamivudine, 3TC GlaxoWellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor);also with AZT Lobucavir Bristol-Myers Squibb CMV infection NelfinavirAgouron HIV infection, Pharmaceuticals AIDS, ARC (protease inhibitor)Nevirapine Boeheringer HIV infection, Ingleheim AIDS, ARC (RT inhibitor)Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH) Peptide TPeninsula Labs AIDS Octapeptide (Belmont, CA) Sequence Trisodium AstraPharm. CMV retinitis, HIV Phosphonoformate Products, Inc. infection,other CMV infections PNU-140690 Pharmacia Upjohn HIV infection, AIDS,ARC (protease inhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4Sheffield Med. HIV infection, Tech (Houston, TX) AIDS, ARC RitonavirAbbott HIV infection, AIDS, ARC (protease inhibitor) SaquinavirHoffmann- HIV infection, LaRoche AIDS, ARC (protease inhibitor)Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS, Didehydrodeoxy-ARC Thymidine Tipranavir Boehringer Ingelheim HIV infection, AIDS, ARC(protease inhibitor) Valaciclovir Glaxo Wellcome Genital HSV & CMVinfections Virazole Viratek/ICN asymptomatic HIV Ribavirin (Costa Mesa,CA) positive, LAS, ARC VX-478 Vertex HIV infection, AIDS, ARCZalcitabine Hoffmann-LaRoche HIV infection, AIDS, ARC, with AZTZidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi'ssarcoma, in combination with other therapies Tenofovir disoproxil,Gilead HIV infection, fumarate salt (VIREAD ®) AIDS, (reversetranscriptase inhibitor) EMTRIVA ® (Emtricitabine) Gilead HIV infection,(FTC) AIDS, (reverse transcriptase inhibitor) COMBIVIR ® GSK HIVinfection, AIDS, (reverse transcriptase inhibitor) Abacavir succinateGSK HIV infection, (or ZIAGEN ®) AIDS, (reverse transcriptase inhibitor)REYATAZ ® Bristol-Myers Squibb HIV infection (or atazanavir) AIDs,protease inhibitor FUZEON ® Roche/Trimeris HIV infection (Enfuvirtide orT-20) AIDs, viral Fusion inhibitor LEXIVA ® GSK/Vertex HIV infection (orFosamprenavir calcium) AIDs, viral protease inhibitor SELZENTRY ® PfizerHIV infection Maraviroc; (UK 427857) AIDs, (CCR5 antagonist, indevelopment) TRIZIVIR ® GSK HIV infection AIDs, (three drug combination)Sch-417690 (vicriviroc) Schering-Plough HIV infection AIDs, (CCR5antagonist, in development) TAK-652 Takeda HIV infection AIDs, (CCR5antagonist, in development) GSK 873140 GSK/ONO HIV infection (ONO-4128)AIDs, (CCR5 antagonist, in development) Integrase Inhibitor Merck HIVinfection MK-0518 AIDs Raltegravir TRUVADA ® Gilead Combination ofTenofovir disoproxil fumarate salt (VIREAD ®) and EMTRIVA ®(Emtricitabine) Integrase Inhibitor Gilead/Japan Tobacco HIV InfectionGS917/JTK-303 AIDs Elvitegravir in development Triple drug combinationGilead/Bristol-Myers Squibb Combination of Tenofovir ATRIPLA ®disoproxil fumarate salt (VIREAD ®), EMTRIVA ® (Emtricitabine), andSUSTIVA ® (Efavirenz) FESTINAVIR ® Oncolys BioPharma HIV infection4′-ethynyl-d4T BMS AIDs in development CMX-157 Chimerix HIV infectionLipid conjugate of AIDs nucleotide tenofovir GSK1349572 GSK HIVinfection Integrase inhibitor AIDs

IMMUNOMODULATORS Drug Name Manufacturer Indication AS-101 Wyeth-AyerstAIDS Bropirimine Pharmacia Upjohn Advanced AIDS Acemannan CarringtonLabs, Inc. AIDS, ARC (Irving, TX) CL246,738 Wyeth AIDS, Kaposi's LederleLabs sarcoma FP-21399 Fuki ImmunoPharm Blocks HIV fusion with CD4+ cellsGamma Interferon Genentech ARC, in combination w/TNF (tumor necrosisfactor) Granulocyte Genetics Institute AIDS Macrophage Colony SandozStimulating Factor Granulocyte Hoechst-Roussel AIDS Macrophage ColonyImmunex Stimulating Factor Granulocyte Schering-Plough AIDS, MacrophageColony combination Stimulating Factor w/AZT HIV Core Particle RorerSeropositive HIV Immunostimulant IL-2 Cetus AIDS, in combinationInterleukin-2 w/AZT IL-2 Hoffman-LaRoche AIDS, ARC, HIV, inInterleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase inInterleukin-2 CD4 cell counts (aldeslukin) Immune Globulin CutterBiological Pediatric AIDS, in Intravenous (Berkeley, CA) combinationw/AZT (human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma,ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC,PGL Imuthiol Diethyl Merieux Institute AIDS, ARC Dithio CarbamateAlpha-2 Schering Plough Kaposi's sarcoma Interferon w/AZT, AIDSMethionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL) MTP-PECiba-Geigy Corp. Kaposi's sarcoma Muramyl-Tripeptide Granulocyte AmgenAIDS, in combination Colony Stimulating w/AZT Factor Remune ImmuneResponse Immunotherapeutic Corp. rCD4 Genentech AIDS, ARC RecombinantSoluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS,ARC Soluble Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma Alfa2a AIDS, ARC, in combination w/AZT SK&F106528 Smith Kline HIV infectionSoluble T4 Thymopentin Immunobiology HIV infection Research Institute(Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNFw/gamma Interferon

ANTI-INFECTIVES Drug Name Manufacturer Indication Clindamycin withPharmacia Upjohn PCP Primaquine Fluconazole Pfizer Cryptococcalmeningitis, candidiasis Pastille Squibb Corp. Prevention of NystatinPastille oral candidiasis Ornidyl Merrell Dow PCP EflornithinePentamidine LyphoMed PCP treatment Isethionate (IM & IV) (Rosemont, IL)Trimethoprim Antibacterial Trimethoprim/sulfa Antibacterial PiritreximBurroughs Wellcome PCP treatment Pentamidine Fisons Corporation PCPprophylaxis Isethionate for Inhalation Spiramycin Rhone-PoulencCryptosporidial diarrhea Intraconazole- Janssen-Pharm. Histoplasmosis;R51211 cryptococcal meningitis Trimetrexate Warner-Lambert PCPDaunorubicin NeXstar, Sequus Kaposi's sarcoma Recombinant Human OrthoPharm. Corp. Severe anemia Erythropoietin assoc. with AZT therapyRecombinant Human Serono AIDS-related Growth Hormone wasting, cachexiaMegestrol Acetate Bristol-Myers Squibb Treatment of anorexia assoc.W/AIDS Testosterone Alza, Smith Kline AIDS-related wasting Total EnteralNorwich Eaton Diarrhea and Nutrition Pharmaceuticals malabsorptionrelated to AIDS

Additionally, the compounds of the disclosure herein set forth may beused in combination with HIV entry inhibitors. Examples of such HIVentry inhibitors are discussed in DRUGS OF THE FUTURE 1999, 24(12), pp.1355-1362; CELL, Vol. 9, pp. 243-246, Oct. 29, 1999; and DRUG DISCOVERYTODAY, Vol. 5, No. 5, May 2000, pp. 183-194 and Inhibitors of the entryof HIV into host cells. Meanwell, Nicholas A.; Kadow, John F. CurrentOpinion in Drug Discovery & Development (2003), 6(4), 451-461.Specifically the compounds can be utilized in combination withattachment inhibitors, fusion inhibitors, and chemokine receptorantagonists aimed at either the CCR5 or CXCR4 coreceptor. HIV attachmentinhibitors are also set forth in U.S. Pat. No. 7,354,924 and U.S. Pat.No. 7,745,625.

It will be understood that the scope of combinations of the compounds ofthis application with AIDS antivirals, immunomodulators,anti-infectives, HIV entry inhibitors or vaccines is not limited to thelist in the above Table but includes, in principle, any combination withany pharmaceutical composition useful for the treatment of AIDS.

Preferred combinations are simultaneous or alternating treatments with acompound of the present disclosure and an inhibitor of HIV proteaseand/or a non-nucleoside inhibitor of HIV reverse transcriptase. Anoptional fourth component in the combination is a nucleoside inhibitorof HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. A preferredinhibitor of HIV protease is REYATAZ® (active ingredient Atazanavir).Typically a dose of 300 to 600 mg is administered once a day. This maybe co-administered with a low dose of Ritonavir (50 to 500 mgs). Anotherpreferred inhibitor of HIV protease is KALETRA®. Another usefulinhibitor of HIV protease is indinavir, which is the sulfate salt ofN-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)—N′-(t-butylcarboxamido)-piperazinyl))-pentaneamideethanolate, and is synthesized according to U.S. Pat. No. 5,413,999.Indinavir is generally administered at a dosage of 800 mg three times aday. Other preferred protease inhibitors are nelfinavir and ritonavir.Another preferred inhibitor of HIV protease is saquinavir which isadministered in a dosage of 600 or 1200 mg tid. Preferred non-nucleosideinhibitors of HIV reverse transcriptase include efavirenz. Thesecombinations may have unexpected effects on limiting the spread anddegree of infection of HIV. Preferred combinations include those withthe following (1) indinavir with efavirenz, and, optionally, AZT and/or3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/or ddIand/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3)stavudine and 3TC and/or zidovudine; (4) tenofovir disoproxil fumaratesalt and emtricitabine.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

General Chemistry (Methods of Synthesis)

The present invention comprises compounds of Formulas I, II, and III,their pharmaceutical formulations, and their use in patients sufferingfrom or susceptible to HIV infection. The compounds of Formulas I, II,and III also include pharmaceutically acceptable salts thereof. Generalprocedures to construct compounds of Formulas I, II, and III andintermediates useful for their synthesis are described in the followingSchemes (after the Abbreviations).

Abbreviations

One or more of the following abbreviations, most of which areconventional abbreviations well known to those skilled in the art, maybe used throughout the description of the disclosure and the examples:

Bz₂O=benzoic anhydrideTBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborateHATU=2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate methanaminiumDCE=dichloroethaneDCM=dichloromethaneCDI=carbonyl diimidazoleprep. HPLC=preparative high performance liquid chromatographyrt=room temperatureDIPEA=diisopropylethylamineDMAP=4-dimethylaminopyridineDMSO=dimethylsulfoxideTHF=tetrahydrofuranKHMDS=potassium bis(trimethylsilyl)amidemin=minute(s)h=hour(s)sat.=saturatedTEA=triethylamineEtOAc=ethyl acetateTFA=trifluoroacetic acidPCC=pyridinium chlorochromateTLC=thin layer chromatographyTf₂NPh=(trifluoromethylsulfonyl)methanesulfonamidedioxane=1,4-dioxanePG=protective groupatm=atmosphere(s)mol=mole(s)mmol=milimole(s)mg=milligram(s)μg=microgram(s)μl=microliter(s)μm=micrometer(s)mm=millimeter(s)HOAc=acetic acidMeOH=methanol

DMF=N,N-dimethylformamide

TBAF=tetrabutylammonium fluorideTBDMSCl=tert-butyldimethylsilyl chlorideThe terms “C-3” and “C-28” refer to certain positions of a triterpenecore as numbered in accordance with IUPAC rules (positions depictedbelow with respect to an illustrative triterpene: betulin):

The same numbering is maintained when referring to the compound seriesin schemes and general descriptions of methods.

Preparation of Compounds of Formulas I, II and III General ChemistrySchemes

Compounds of Formula I can be prepared from commercially available(Aldrich, others) betulinic acid by chemistry described in the followingschemes. Compounds of Formula II and III are described thereafter.

General Reaction Schemes are Set Forth as Follows:

Scheme 1 describes the preparation of the key intermediate C-17 primaryamine from betulinic acid. The carboxylic acid present in betulinic acidwas protected with a suitable protective group. Standard oxidation (i.e.PCC, Dess-Martin) of the C-3 hydroxyl group produces the C-3 ketonewhich is then converted into the triflate using conditions know to thoseskilled in the art. Palladium-catalyzed cross coupling with a boronicacid derivative (Stille coupling using stannanes can also be used)afforded the corresponding C-3-modified betulinic acid derivatives. TheC-28 carboxylic ester was then selectively deprotected and submitted toCurtius rearrangement conditions to afford the C-17 primary amine. Thisreaction can be carried out in one single step or stepwise via isolationof the isocyanate intermediate, as shown in Scheme 1.

The isocyanate can be further modified to prepare ureas as shown inScheme 2. Addition of an amine to a solution of the isocyanate in asolvent such as THF or dioxane in the presence of Hunig's base or TEA atroom temperature or heating if necessary, affords the corresponding C-17urea. Hydrolysis of the benzoic ester affords the benzoic acidderivative.

Similarly, carbamates can be prepared by adding an alcohol to theisocyanate in a solution of THF or dioxane in the presence of a basesuch as sodium hydride at room temperature or heating when necessaryfollowed by hydrolysis of the carboxylic ester. The deprotection mayalso happen under the conditions of the first reaction, so no additionalstep may be needed.The C-17 primary amine can be further modified using standard methods,known to those skill in the art. Some examples are shown in thefollowing schemes.

C-17 amides can be prepared by reacting a carboxylic acid with the C-17primary amine in the presence of an adequate coupling reagent such asHATU, DCC, and others known to those skilled in the art, in the presenceof a base such as Hunig's base, TEA, etc., in the appropriate solvent(DCM, THF, DMF, etc.). Hydrolysis of the carboxylic ester affords thebenzoic acid. Alternatively, some amides can be prepared by treating theC-17 primary amine with the corresponding carboxylic acid chloridereagent instead of an acid. Similarly, sulfonamides can be prepared fromthe C-17 primary amine by using a sulfonyl chloride as the sulfonylatingagent.

The C-17 primary amine can be treated with an aldehyde under reductiveamination conditions (e.g. NaBH(OAc)₃) in the presence of AcOH/NaOAc orTi(OPr)₄ in a solvent such as THF, 1,4-dioxane, DCE or DCM) to affordC-17 secondary amines Hydrolysis of the carboxylic ester renders thebenzoic acid compound.

Some C-17 amines can be prepared by alkylation of the C-17 primary aminewith an alkylating agent (R-LG), where LG is a leaving group such as,but not limited to Br, Cl, I, mesylate, tosylate or triflate in thepresence of a base. Heating may be needed in some cases. Hydrolysis ofthe carboxylic ester renders the benzoic acid product.

In some cases, by prolonging the reaction times and heating the reactionmixture, the dialkylated product can also be formed.

Alternatively, some C-17 amines can be prepared by 1,4-addition toMichael acceptors followed by hydrolysis of the ester.Substituents R, R′ and R″ may contain functional groups (i.e. COOH,COOR, OH, NHR) that can be further modified by methods know to thoseskilled in the art. The modification can be carried out before or afterthe final deprotection of the carboxylic acid is performed depending onthe nature of the functional group.Alternatively, the C-17 secondary amine can be further modified (i.e.alkylated, acylated, sulfonylated, etc.) using some of the methodsdescribed above or other standard methods known to those skilled in theart. Saturation of the isopropenyl group can be accomplished byhydrogenation under standard conditions of the final products.

The benzoic acid can be further modified by methods known to thoseskilled in the art. An example of such modifications is shown in scheme9: The free benzoic acid can be converted into the corresponding acidchloride and then treated with the corresponding nucleophile, forexample a sulfonyl amide or urea sulfamide, in the presence of a base toafford a sulfonyl amide or acylsulfamide derivative.Compounds of formula I where the modification in the C-3 positiondiffers from benzoic acid can be prepared by selecting the correspondingboronic acid in the palladium-catalyzed cross coupling step shown inScheme 1 (Scheme 10). Then the C-28 position can be modified using thechemistry methods described in the above schemes to obtain thecorresponding C-17 amino derivatives.

Alternatively, compounds of formula I can be prepared from betulinicacid as described in Scheme 11. Curtius rearrangement of betulinic acidcan be accomplished without protection of the C-3 hydroxyl group torender the C-17 isocyanate which upon acid hydrolysis affords the C-17amine. The C-17 amine is then selectively protected with an amineprotective group (i.e F-moc, Boc) to then perform the oxidation of theC-3 hydroxy group to a ketone under standard conditions (i.e. PCC,Dess-Martin reagent, etc). Conversion of the ketone into its triflatecan be accomplished by methods known to those skilled in the art. Theprotective group in the amino group is then taken off to produce theC-17 unsubstituted amine Installation of the C-3 moiety is accomplishedvia Suzuki coupling of the triflate with the corresponding boronic acidas described above. The C-17 amino group can then be derivatized asshown above in previous schemes (alkyaltion, acylation, etc).

Compounds of formula II can be prepared using the chemistry methodsdescribed above for compounds of formula I, with one extra step whichconsists of saturation of the double bonds, as shown below in Scheme 12:

Compounds of formula III can be prepared in the same manner describedabove for compounds of formula I and II using oleanoic or ursolic acidas starting materials instead of betulinic acid.

EXAMPLES

The following examples illustrate typical syntheses of the compounds ofFormulas I, II and III as described generally above. These examples areillustrative only and are not intended to limit the disclosure in anyway. The reagents and starting materials are readily available to one ofordinary skill in the art.

Chemistry Typical Procedures and Characterization of Selected Examples:

Unless otherwise stated, solvents and reagents were used directly asobtained from commercial sources, and reactions were performed under anitrogen atmosphere. Flash chromatography was conducted on Silica gel 60(0.040-0.063 particle size; EM Science supply). ¹H NMR spectra wererecorded on Bruker DRX-500f at 500 MHz (or Bruker AV 400 MHz, BrukerDPX-300B or Varian Gemini 300 at 300 MHz as stated). The chemical shiftswere reported in ppm on the δ scale relative to δTMS=0. The followinginternal references were used for the residual protons in the followingsolvents: CDCl₃ (δ_(H) 7.26), CD₃OD (δ_(H) 3.30), Acetic-d4 (Acetic Acidd₄) (δ_(H) 11.6, 2.07), DMSO mix or DMSO-D6_CDCl₃ ((_(H) 2.50 and 8.25)(ratio 75%:25%), and DMSO-D6 (δ_(H) 2.50). Standard acronyms wereemployed to describe the multiplicity patterns: s (singlet), br. s(broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet), b(broad), app (apparent). The coupling constant (J) is in Hertz. AllLiquid Chromatography (LC) data were recorded on a Shimadzu LC-10ASliquid chromatograph using a SPD-10AV UV-Vis detector with MassSpectrometry (MS) data determined using a Micromass Platform for LC inelectrospray mode.

LC/MS methods:

Method 1

Start % B=0, Final % B=100 over 2 minute gradient, hold at 100% BFlow Rate=4 mL/min

Wavelength=220 nm

Solvent A=95% water, 5% methanol, 10 mM ammonium acetateSolvent B=5% water, 95% methanol, 10 mM ammonium acetate

Column=Phenomenex Luna C18, 5 μm, 3.0×50 mm Method 2

Start % B=0, Final % B=100 over 2 minute gradient, hold at 100% BFlow Rate=1 mL/min

Wavelength=220 nm

Solvent A=90% water, 10% acetonitrile, 0.1% TFASolvent B=10% water, 90% acetonitrile, 0.1% TFA

Column=Phenomenex Luna C18, 3 μm, 2.0×30 mm Method 3

Start % B=0, Final % B=100 over 2 minute gradient, hold at 100% BFlow Rate=4 mL/min

Wavelength=220 nm

Solvent A=95% water, 5% methanol, 10 mM ammonium acetateSolvent B=5% water, 95% methanol, 10 mM ammonium acetate

Column=Waters Xbridge C18, 5 μm, 4.6×50 mm Method 4

Start % B=0, Final % B=100 over 2 minute gradient, hold at 100% BFlow Rate=0.8 mL/min

Wavelength=220 nm

Solvent A=95% water, 5% methanol, 10 mM ammonium acetateSolvent B=5% water, 95% methanol, 10 mM ammonium acetate

Column=Waters Xbridge C18, 3.5 μm, 2.1×50 mm Method 5

Start % B=15, Final % B=100 over 2 minute gradient, hold at 100% BFlow Rate=1 mL/min

Wavelength=220 nm

Solvent A=95% water, 5% acetonitrile, 10 mM ammonium acetateSolvent B=5% water, 95% acetonitrile, 10 mM ammonium acetate

Column=Phenomenex Luna C18, 3 μm, 2.0×30 mm Method 6

Start % B=0, Final % B=100 over 2 minute gradient, hold at 100% BFlow Rate=1 ml/min

Wavelength=220 nm

Solvent A=95% water, 5% acetonitrile, 10 mM ammonium acetateSolvent B=5% water, 95% acetonitrile, 10 mM ammonium acetate

Column=Phenomenex Luna C18, 3 μm, 2.0×30 mm Method 7

Start % B=25, Final % B=100 over 2 minute gradient, hold at 100% BFlow Rate=1 ml/min

Wavelength=220 nm

Solvent A=95% water, 5% acetonitrile, 10 mM ammonium acetateSolvent B=5% water, 95% acetonitrile, 10 mM ammonium acetate

Column=Phenomenex Luna C18, 3 μm, 2.0×30 mm Method 8

Start % B=0, Final % B=100 over 4 minute gradient, hold at 100% BFlow Rate=5 ml/min

Wavelength=220 nm

Solvent A=90% water, 10% methanol, 0.1% TFASolvent B=10% water, 90% methanol, 0.1% TFA

Column=Phenomenex Luna C18, 10 μm 3.0×50 mm Method 9

Start % B=20, Final % B=100 over 2 minute gradient, hold at 100% BFlow Rate=1 ml/min

Wavelength=220 nm

Solvent A=95% water, 5% acetonitrile, 10 mM ammonium acetateSolvent B=5% water, 95% acetonitrile, 10 mM ammonium acetate

Column=Phenomenex Luna C18, 3 μm, 2.0×30 mm Method 10

Start % B=0, Final % B=100 over 2 minute gradient, hold at 100% BFlow Rate=1 mL/min

Wavelength=220 nm

Solvent A=95% water, 5% methanol, 10 mM ammonium acetateSolvent B=5% water, 95% methanol, 10 mM ammonium acetate

Column=Phenomenex Luna C18, 3 μm, 2.0×30 mm Method 11

Start % B=0, Final % B=100 over 2 minute gradient, hold at 100% BFlow Rate=1 mL/min

Wavelength=220 nm

Solvent A=90% water, 10% methanol, 0.1% TFASolvent B=10% water, 90% methanol, 0.1% TFA

Column=Phenomenex Luna C18, 3 μm, 2.0×30 mm Method 12

Start % B=30, Final % B=100 over 1 minute gradientFlow Rate=0.8 mL/min

Wavelength=220 nm

Solvent A=90% water, 10% methanol, 0.1% TFASolvent B=10% water, 90% methanol, 0.1% TFA

Column=Xbridge Phenyl 2.1×50 mm 2.5 μm Method 13

Start % B=20, Final % B=100 over 2 minute gradientFlow Rate=0.8 mL/min

Wavelength=254 nm

Solvent A=90% water, 10% methanol, 0.1% TFASolvent B=10% water, 90% methanol, 0.1% TFA

Column=Xbridge Phenyl 2.1×50 mm 2.5 μm Method 14

Start % B=0, Final % B=100 over 4 minute gradient, hold at 100% BFlow Rate=1 mL/min

Wavelength=220 nm

Solvent A=95% water, 5% acetonitrile, 10 mM ammonium acetateSolvent B=5% water, 95% acetonitrile, 10 mM ammonium acetate

Column=Waters BEH C18, 1.7 μm, 2.0×50 mm Method 15

Start % B=0, Final % B=100 over 4 minute gradient, hold at 100% BFlow Rate=0.5 mL/min

Wavelength=220 nm

Solvent A=95% water, 5% methanol, 10 mM ammonium acetateSolvent B=5% water, 95% methanol, 10 mM ammonium acetate

Column=Waters BEH C18, 1.7 μm, 2.0×50 mm Method 16

Start % B=0, Final % B=100 over 4 minute gradient, hold at 100% BFlow Rate=1 mL/min

Wavelength=220 nm

Solvent A=90% water, 10% methanol, 0.1% TFASolvent B=10% water, 90% methanol, 0.1% TFA

Column=Phenomenex Luna C18, 3 μm, 2.0×30 mm Method 17

Start % B=10%, Final % B=100 over 1 minute gradient, hold at 100% BFlow Rate=0.8 mL/min

Wavelength=220 nm

Solvent A=90% water, 10% methanol, 0.1% TFASolvent B=10% water, 90% methanol, 0.1% TFA

Column=Phenomenex-luna, 2.0×30 mm, 3.0 μm Prep HPLC Methods: Prep HPLCMethod 1

Start % B=35, Final % B=100 over 10 minute gradient, hold at 100% B for8 minutesFlow Rate=100 mL/minSolvent A=90% water, 10% acetonitrile, 0.1% TFASolvent B=10% water, 90% acetonitrile, 0.1% TFA

Column=Phenomenex Luna C8(2), 10 μm, 50×250 mm (100A) Prep HPLC Method 2

Start % B=15, Final % B=100 over 12 minute gradient, hold at 100% B for6 minutesFlow Rate=50 mL/minSolvent A=90% water, 10% acetonitrile, 0.1% TFASolvent B=10% water, 90% acetonitrile, 0.1% TFA

Column=Waters Sunfire C18, 5 μm, 30×100 mm Prep HPLC Method 3

Start % B=20, Final % B=100 over 8 minute gradient, hold at 100% B for10 minutesFlow Rate=50 mL/minSolvent A=90% water, 10% acetonitrile, 0.1% TFASolvent B=10% water, 90% acetonitrile, 0.1% TFA

Column=Waters Sunfire C18, 5 μm, 30×100 mm Prep HPLC Method 4

Start % B=20, Final % B=100 over 15 minute gradient, hold at 100% B for8 minutesFlow Rate=100 mL/minSolvent A=90% water, 10% acetonitrile, 0.1% TFASolvent B=10% water, 90% acetonitrile, 0.1% TFA

Column=Phenomenex Luna C8(2), 10 μm, 50×250 mm (100A) Prep HPLC Method5:

Start % B=15, Final % B=100 over 20 minute gradient, hold at 100% B for4 minutesFlow Rate=50 mL/minSolvent A=90% water, 10% acetonitrile, 0.1% TFASolvent B=10% water, 90% acetonitrile, 0.1% TFA

Column=Waters Sunfire C18, 5 μm, 30×100 mm Prep HPLC Method 6

Start % B=30, Final % B=100 over 20 minute gradient, hold at 100% B for6 minutesFlow Rate=40 mL/minSolvent A=90% water, 10% methanol, 0.1% TFASolvent B=10% water, 90% methanol, 0.1% TFA

Column=Phenomenex Luna C18(2), 5 μm, 30×100 mm Prep HPLC Method 7

Start % B=0, Final % B=100 over 30 minute gradient, hold at 100% B for 8minutesFlow Rate=50 mL/minSolvent A=90% water, 10% acetonitrile, 0.1% TFASolvent B=10% water, 90% acetonitrile, 0.1% TFA

Column=Waters Xbridge Phenyl, 5 μm, 30×100 mm Prep HPLC Method 8

Start % B=0, Final % B=100 over 15 minute gradient, hold at 100% B for10 minutesFlow Rate=50 mL/minSolvent A=90% water, 10% acetonitrile, 0.1% TFASolvent B=10% water, 90% acetonitrile, 0.1% TFA

Column=Waters Xbridge Phenyl, 5 μm, 30×100 mm Prep HPLC Method 9

Start % B=30, Final % B=100 over 20 minute gradient, hold at 100% B for10 minutesFlow Rate=50 mL/minSolvent A=90% water, 10% acetonitrile, 0.1% TFASolvent B=10% water, 90% acetonitrile, 0.1% TFA

Column=Waters Sunfire C18, 5 μm, 30×100 mm Prep HPLC Method 10

Start % B=0, Final % B=100 over 20 minute gradient, hold at 100% B for 4minutesFlow Rate=50 mL/minSolvent A=90% water, 10% acetonitrile, 0.1% TFASolvent B=10% water, 90% acetonitrile, 0.1% TFA

Column=Waters Xbridge Phenyl, 5 μm, 30×100 mm Prep HPLC Method 11

Start % B=20, Final % B=100 over 10 min gradient, hold at 100% B for 15minFlow Rate=50 ml/min

Wavelength=220 Solvent Pair=Water—Methanol—TFA Solvent A=90% Water—10%Methanol—0.1% TFA Solvent B=10% Water—90% Methanol—0.1% TFAColumn=Waters Sunfire C18, 5 μm, 30×150 mm Analytical HPLC Methods:Analytical HPLC Method 1 Start % B=10 Final % B=100 Gradient Time=15 min

Flow Rate=1 ml/min

Wavelength1=220 Wavelength2=254

Solvent A=10 mM amm. bicarb (pH=9.5)/95% water/5% methanolSolvent B=10 mM amm. bicarb (pH=9.5)/5% water/95% methanol

Column=Xbridge Phenyl 3.5 um, 3.0×150 mm Analytical HPLC Method 2 Start% B=10 Final % B=100 Gradient Time=15 min

Flow Rate=1 ml/min

Wavelength1=220 Wavelength2=254

Solvent A=0.1% TFA/95% water/5% acetonitrileSolvent B=0.1% TFA/5% water/95% acetonitrile

Column=Xbridge Phenyl 3.5 um, 3.0×150 mm Preparation of Compounds

Preparation of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-benzyl9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylate

To a suspension of betulinic acid (12 g, 26.3 mmol) and potassiumcarbonate (7.26 g, 52.6 mmol) in DMF (150 mL) was added benzyl bromide(3.28 mL, 27.6 mmol). The mixture was heated to 60° C. for 3.5 h, andthen it was cooled to rt. Solids started to precipitate upon cooling.The mixture was diluted water (200 mL) and the solids that formed werecollected by filtration to give the title compound (13.92 g, 25.5 mmol,97% yield) as a white solid. ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm7.39-7.28 (m, 5H), 5.16-5.06 (m, 2H), 4.71 (d, J=1.83 Hz, 1H), 4.59 (s,1H), 3.17 (ddd, J=11.44, 5.65, 5.49 Hz, 1H), 3.01 (td, J=10.99, 4.88 Hz,1H), 2.27 (ddd, J=12.36, 3.20, 3.05 Hz, 1H), 2.21-2.13 (m, 1H),1.93-1.81 (m, 2H), 1.67 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H), 1.71-0.82(m, 20H), 0.79 (s, 3H), 0.75 (s, 3H), 0.74 (s, 3H).

Preparation of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-benzyl5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylate

To a solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-benzyl9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylate(7.1 g, 12.98 mmol) in dichloromethane (100 mL) was added PCC (4.20 g,19.48 mmol). After stirring for five minutes, the mixture turned a deepcrimson color. The mixture was further stirred for 5.5 h. The mixturewas filtered through a pad of celite and silica gel which was washedwith dichloromethane and then with a 1:1 mixture of ethylacetate:hexanes. The filtrate was concentrated under reduced pressure togive the title compound (6.92 g, 12.7 mmol, 98% yield) as a white foam.¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.38-7.28 (m, 5H), 5.17-5.06 (m,2H), 4.72 (d, J=1.83 Hz, 1H), 4.59 (s, 1H), 3.01 (td, J=10.99, 4.88 Hz,1H), 2.51-2.43 (m, 1H), 2.42-2.34 (m, 1H), 2.28 (dt, J=12.59, 3.17 Hz,1H), 2.21 (td, J=12.28, 3.51 Hz, 1H), 1.94-1.82 (m, 3H), 1.67 (s, 3H),1.05 (s, 3H), 1.01 (s, 3H), 1.73-0.95 (m, 17H), 0.94 (s, 3H), 0.89 (s,3H), 0.78 (s, 3H).

Preparation of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-benzyl5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-9-(trifluoromethylsulfonyloxy)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate

A solution of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-benzyl5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylate(29.0 g, 53.2 mmol) in THF (200 mL) was cooled to −78° C. To thesolution was added KHMDS (0.5 M in toluene) (213 mL, 106 mmol). Theyellow solution was stirred at −78° C. for 25 minutes and a solution of1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl)sulfonyl methanesulfonamide(20.92 g, 58.6 mmol) in THF (70 mL) and toluene (30 mL) was added viacannula. The solution was stirred at −78° C. for 3 h. Then, anadditional 1.0 g of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl)sulfonylmethanesulfonamide was added and the mixture was stirred at −78° C.After stirring for 1 h, the mixture was quenched with water (300 mL) andthe mixture was extracted with ethyl acetate (3×200 mL). The combinedorganic layers were dried with MgSO₄. The drying agent was removed byfiltration, and the filtrate was concentrated under reduced pressure togive the title compound (40.0 g, 59.1 mmol) as a yellow solid. ProductRf=0.57 by silica gel TLC, 5% EtOAc in hexanes, visualized usingHanessian's stain. ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.29-7.41 (m,5H), 5.54 (dd, J=6.71, 1.53 Hz, 1H), 5.13-5.18 (m, 1H), 5.05-5.12 (m,1H), 4.72 (d, J=1.53 Hz, 1H), 4.59 (s, 1H), 3.02 (td, J=10.99, 4.58 Hz,1H), 2.25-2.31 (m, 1H), 2.22 (td, J=12.21, 3.36 Hz, 1H), 2.14 (dd,J=17.09, 6.71 Hz, 1H), 1.81-1.96 (m, 2H), 1.67 (s, 3H), 1.10 (s, 3H),1.00 (s, 3H), 0.94 (s, 3H), 0.91-1.77 (m, 17H), 0.88 (s, 3H), 0.77 (s,3H).

Preparation of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-benzyl9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate

To a solution of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13bR)-benzyl5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-9-(trifluoromethylsulfonyloxy)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate(6.21 g, 9.18 mmol) in dioxane (25 mL) was added 2-propanol (25 mL) andwater (15 mL) followed by sodium carbonate monohydrate (3.42 g, 27.5mmol), 4-methoxycarbonylphenylboronic acid (2.478 g, 13.77 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.318 g, 0.275 mmol). Theflask was attached to a reflux condenser, flushed with N₂ and heated toreflux overnight. The mixture was then cooled to rt and diluted withwater (75 mL). The mixture was extracted with ethyl acetate (3×75 mL)and washed with brine (75 mL). The combined organic layers were driedwith MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was adsorbed to silica gel and purified by silica gel flashchromatography using a 0-20% ethyl acetate in hexanes gradient. Thefractions containing the expected product were combined and concentratedunder reduced pressure to give the title compound (4.16 g, 6.28 mmol,68.4% yield) as a white foam. ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.92(d, J=8.24 Hz, 2H), 7.40-7.29 (m, 5H), 7.19 (d, J=8.24 Hz, 2H), 5.28(dd, J=6.10, 1.83 Hz, 1H), 5.19-5.07 (m, 2H), 4.73 (d, J=1.83 Hz, 1H),4.60 (s, 1H), 3.90 (s, 3H), 3.04 (td, J=10.91, 4.73 Hz, 1H), 2.20-2.32(m, 2H), 2.09 (dd, J=17.24, 6.26 Hz, 1H), 1.95-1.82 (m, 2H), 1.69 (s,3H), 0.97 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H), 0.91 (s, 3H), 1.75-0.87(m, 17H), 0.82 (s, 3H).

Preparation of(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-tert-butyldimethylsilyl9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate

To a solution of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-benzyl9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate(3.82 g, 5.76 mmol) in dichloroethane (100 mL) was added triethylamine(1.285 mL, 9.22 mmol), tert-butyldimethylsilane (1.912 mL, 11.52 mmol),and palladium(II) acetate (0.647 g, 2.88 mmol). The mixture was flushedwith N₂ and heated to 60° C. After 2 h, the reaction was cooled to rt,filtered through a pad of celite and silica gel to remove the solidswhich were washed with 25% EtOAc in hexanes. The filtrate wasconcentrated under reduced pressure and treated with acetic acid (25mL), THF (10 mL) and water (3 mL). After stirring for 1 h the solidsformed were collected by filtration and washed with water to give thetitle compound (3.62 g, 5.27 mmol, 91% yield) as a white solid. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 7.94 (d, J=8.28 Hz, 2H), 7.21 (d, J=8.28Hz, 2H), 5.30 (dd, J=6.15, 1.63 Hz, 1H), 4.75 (d, J=1.76 Hz, 1H), 4.62(s, 1H), 3.92 (s, 4H), 3.08 (td, J=10.92, 4.27 Hz, 1H), 2.35-2.22 (m,2H), 2.17-2.06 (m, 1H), 2.02-1.84 (m, 2H), 1.71 (s, 3H), 1.01 (s, 6H),0.99 (br. s., 3H), 0.98 (s, 9H), 0.94 (s, 6H), 1.78-0.90 (m, 16H),0.32-0.28 (m, 6H).

Preparation of(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylicacid

To solution of(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-tert-butyldimethylsilyl9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate(3.12 g, 4.54 mmol) in dioxane (25 mL) was added TBAF (75% wt in water)(2.375 g, 6.81 mmol) and the mixture was stirred at rt for 4 h. Thereaction mixture was diluted with 1N HCl (25 mL) and water (5 mL) andextracted with dichloromethane (3×100 mL). The combined organic layerswere dried over Na₂SO₄, filtered, and partially concentrated underreduced pressure to about 10 mL volume. To the partially concentratedmixture was added 1N HCl (50 mL). The solids that formed were collectedby filtration and washed with water to give the title compound (2.58 g,4.50 mmol, 99% yield) as a white solid. LCMS: m/e 571.47 (M−H)⁻, 3.60min (method 1). ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.80 (br. s., 1H),7.92 (d, J=8.24 Hz, 2H), 7.18 (d, J=8.24 Hz, 2H), 5.32-5.26 (m, 1H),4.75 (s, 1H), 4.62 (br. s., 1H), 3.90 (s, 3H), 3.07-2.99 (m, 1H),2.33-2.21 (m, 2H), 2.10 (dd, J=17.09, 6.10 Hz, 1H), 2.06-1.94 (m, 2H),1.70 (s, 3H), 1.01 (br. s., 3H), 1.00 (br. s., 3H), 0.98 (s, 3H), 0.91(s, 6H), 1.79-0.89 (m, 17H).

Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a slurry of(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylicacid (10 g, 17.46 mmol) in 1,4-dioxane (200 mL) was added triethylamine(4.38 mL, 31.4 mmol) followed by diphenyl phosphoryl azide (5.82 mL,26.2 mmol). The resulting white slurry was heated to 100° C. After 5 h,the reaction was allowed to cool to rt and was then diluted with EtOAcand washed with 1N NaOH (2×70 mL). The combined aqueous layer wasextracted with EtOAc (2×150 mL). The combined organic layer was driedover Na₂SO₄, filtered and concentrated to a slurry (75 mL) which wasstored in a refrigerator overnight. The slurry was filtered and thewhite solid product was washed with Et₂O. The liquid filtrate wasconcentrated to a yellow slurry which was filtered and washed with Et₂Oto give more white solid product. The two batches of white solid werecombined and dried in vacuo to give the title compound (8.6 g, 15.09mmol, 86% yield) as a white solid. ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm8.0 (2H, d, J=8.2 Hz), 7.2 (2H, d, J=8.2 Hz), 5.3 (1H, d, J=4.6 Hz), 4.8(1H, s), 4.7 (1H, s), 3.9 (3H, s), 2.6 (1H, td, J=10.8, 5.8 Hz), 2.1-2.2(2H, m), 1.8-2.0 (4H, m), 1.7-1.8 (1H, m), 1.7 (3H, s), 1.5-1.7 (5H, m),1.4-1.5 (5H, m), 1.3-1.4 (2H, m), 1.2-1.3 (2H, m), 1.1 (3H, s), 1.1-1.1(1H, m), 1.0 (3H, s), 1.0 (3H, s), 1.0 (3H, br. s.), 1.0 (3H, br. s.).¹³C NMR (CHLOROFORM-d) δ ppm 14.2, 15.4, 16.2, 19.2, 19.5, 20.8, 21.0,24.7, 27.4, 29.0, 29.2, 33.3, 36.0, 37.2, 39.0, 39.0, 40.3, 41.5, 41.8,47.8, 49.0, 49.2, 51.7, 52.6, 66.8, 71.3, 110.2, 121.3, 123.7, 127.6,128.2, 129.8, 146.0, 148.4, 148.6, 166.9.

Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a cloudy solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(5.47 g, 9.60 mmol) in THF (100 mL) was added concentrated hydrochloricacid (19.83 mL, 240 mmol). The resulting homogeneous mixture was stirredat rt for 72 h, the reaction mixture was concentrated to dryness to givemethyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,HCl (4.98 g, 8.58 mmol, 89% yield) as a white solid. LCMS: m/e 544.5(M+H)⁺, 3.26 min (method 6). ¹H NMR (500 MHz, 1:1 CDCl₃:MeOD, MeOD lock)δ ppm 7.9 (2H, d, J=8.5 Hz), 7.3 (1H, t, J=7.8 Hz), 7.2 (2H, d, J=8.5Hz), 7.1 (1H, t, J=7.3 Hz), 5.3 (1H, d, J=4.6 Hz), 4.8 (1H, s), 4.7 (1H,br. s.), 3.9 (2H, s), 3.6 (2H, dt, J=15.6, 6.6 Hz), 3.3 (1H, dt, J=3.1,1.6 Hz), 2.6 (1H, td, J=11.0, 6.1 Hz), 2.1 (1H, dd, J=17.1, 6.4 Hz), 2.0(1H, d, J=13.4 Hz), 1.9-2.0 (1H, m), 1.8-1.9 (2H, m), 1.7-1.7 (3H, m),1.6-1.7 (3H, m), 1.5-1.6 (3H, m), 1.5-1.5 (2H, m), 1.4 (1H, br. s.),1.3-1.4 (1H, m), 1.2-1.3 (1H, m), 1.1-1.2 (2H, m), 1.1-1.1 (1H, m), 1.0(3H, s), 1.0 (3H, s), 0.9 (3H, s), 0.9 (3H, s).

Example 1 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was formed as a byproduct during the preparation ofmethyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate.Purification by reverse phase preparative HPLC gave an off-white solid(100 mg, 3.5% yield) mono-TFA salt. LCMS: m/z 530 (M+H⁺), retention time2.29 min (method 11). ¹H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD,MeOD lock) δ ppm 0.94 (br. s., 3H) 0.95 (br. s., 3H) 1.02 (s, 3H) 1.06(s, 3H) 1.09-1.22 (m, 4H) 1.22-1.30 (m, 1H) 1.30-1.47 (m, 3H) 1.49-1.57(m, 4H) 1.58-1.72 (m, 6H) 1.73 (s, 3H) 1.74-1.91 (m, 4H) 1.91-1.99 (m,1H) 2.02-2.18 (m, 2H) 2.51-2.63 (m, 1H) 4.71 (s, 1H) 4.81 (s, 1H) 5.29(d, J=4.88 Hz, 1H) 7.20 (d, J=8.24 Hz, 2H) 7.92 (d, J=8.24 Hz, 2H).

Section 1. Ureas Example 2 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1-(tert-butoxycarbonylamino)cyclopropyl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1-(tert-butoxycarbonylamino)cyclopropyl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(600 mg, 1.053 mmol) and N,N-diisopropyethyllamine (0.734 mL, 4.21 mmol)in THF (6 mL) was added tert-butyl 1-(aminomethyl)cyclopropylcarbamate(294 mg, 1.579 mmol). The resulting mixture was stirred at rt. After 16h, the solvent was concentrated. The crude material was dissolved in THF(1 mL) and MeOH (2 mL), filtered and purified by reverse phasepreparative HPLC (method 1) to give the title compound (499.5 mg, 58%yield) as a white solid. LCMS: m/e 756.7 (M+H)⁺, 2.75 min (method 7). ¹HNMR (500 MHz, CHLOROFORM-d) δ ppm 8.0 (2H, d, J=8.5 Hz), 7.2 (2H, d,J=8.5 Hz), 5.3-5.3 (1H, m), 5.1 (1H, br. s.), 4.8 (1H, s), 4.7 (1H, s),3.9 (3H, s), 3.5-3.5 (1H, m), 3.4 (1H, d, J=14.3 Hz), 2.8 (1H, br. s.),2.6 (1H, d, J=12.8 Hz), 2.4 (1H, dd, J=12.2, 8.2 Hz), 2.1 (1H, dd,J=17.4, 6.4 Hz), 1.9-2.1 (2H, m), 1.8 (1H, d, J=13.4 Hz), 1.7-1.8 (1H,m), 1.7 (3H, s), 1.7-1.7 (2H, m), 1.5-1.7 (3H, m), 1.5 (9H, s), 1.4-1.5(5H, m), 1.2-1.3 (1H, m), 1.1-1.2 (2H, m), 1.1 (3H, s), 1.0 (3H, s), 1.0(3H, s), 0.9 (6H, s), 0.8-0.9 (3H, m). ¹³C NMR (CHLOROFORM-d) δ ppm14.1, 15.4, 16.1, 19.0, 19.5, 20.7, 20.8, 24.8, 27.0, 28.1, 29.1, 29.2,29.4, 31.4, 33.2, 35.1, 36.0, 36.6, 37.2, 40.4, 41.4, 41.6, 46.0, 49.1,49.6, 51.7, 52.5, 77.3, 80.1, 109.9, 123.7, 127.6, 128.2, 129.8, 146.0,148.4, 149.2, 167.0.

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1-(tert-butoxycarbonylamino)cyclopropyl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-((1-(tert-butoxycarbonylamino)cyclopropyl)methyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(91 mg, 0.12 mmol) in THF (5 mL) was added a solution of lithiumhydroxide monohydrate (20.2 mg, 0.481 mmol) in water (1.00 mL). Thereaction mixture was stirred at 80° C. for 3 h. The reaction wasconcentrated and purified by reversed phase preparative HPLC using prepHPLC method 2. HPLC fractions containing product peaks were treated withsaturated aqueous NaHCO₃ solution (100 mL), combined and concentrated.The resulting residue was triturated with H₂O (8 mL) and extracted witha mixture of THF (30 mL) and EtOAc (50 mL). The organic layer was washedwith brine, dried over MgSO₄, filtered and concentrated to give thetitle compound (58.1 mg, 0.069 mmol, 57.7% yield) as a white solid.LCMS: m/e 742.6 (M+H)⁺, 2.13 min (method 6). ¹H NMR (500 MHz, MeOD) δppm 7.9 (2H, d, J=7.9 Hz), 7.2 (2H, d, J=8.2 Hz), 5.3 (1H, d, J=6.1 Hz),4.8 (1H, s), 4.6 (1H, s), 3.9-4.0 (1H, m), 3.3 (2H, d, J=9.5 Hz), 2.7(1H, br. s.), 2.6 (1H, d, J=13.4 Hz), 2.4 (1H, dd, J=11.7, 8.7 Hz), 2.2(1H, dd, J=17.2, 6.3 Hz), 1.9-2.0 (3H, m), 1.7-1.8 (2H, m), 1.7 (3H, s),1.7-1.7 (1H, m), 1.5-1.6 (3H, m), 1.5-1.5 (6H, m), 1.5 (9H, s), 1.4 (2H,d, J=2.1 Hz), 1.2-1.4 (6H, m), 1.2 (3H, s), 1.1-1.1 (2H, m), 1.0 (6H,br. s.), 1.0 (3H, s), 1.0 (3H, s), 0.9-0.9 (1H, m). ¹³C NMR (MeOD) δ ppm11.2, 13.9, 15.5, 16.1, 18.4, 18.6, 20.0, 20.7, 21.6, 23.9, 25.6, 27.5,27.8, 29.1, 29.1, 29.8, 29.9, 30.0, 33.8, 35.7, 36.5, 37.6, 37.7, 40.8,41.9, 42.1, 49.9, 49.9, 53.3, 63.8, 67.3, 79.2, 109.5, 124.1, 128.7,130.1, 146.8, 150.4, 157.5, 159.2.

Example 3 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(610.0 mg, 1.071 mmol) in THF (10 mL) was addedN,N-diisopropylethylamine (0.559 mL, 3.21 mmol) andN,N-dimethylethylenediamine (0.353 mL, 3.21 mmol). The reaction mixturewas stirred at 25° C. After 18 h, the reaction mixture was diluted withEtOAc (50 mL) and treated with 1N HCl (5 mL). The mixture wasconcentrated to a paste and then triturated with EtOAc, filtered andwashed with Et₂O. The white solid was saved and the liquid filtrate wasconcentrated and the trituration and filtration steps were repeatedtwice more. The combined white solid product was dried in a vacuum ovento give the title compound (650.0 mg, 0.958 mmol, 90% yield). LCMS: m/e658.4 (M+H)⁺, 4.25 min (method 8). ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm7.9 (2H, d, J=8.5 Hz), 7.2 (2H, d, J=8.2 Hz), 5.3 (1H, dd, J=6.3, 1.7Hz), 4.8 (1H, s), 4.6 (1H, s), 3.9 (3H, s), 3.7-3.8 (1H, m), 3.5-3.6(1H, m), 3.2 (2H, br. s.), 2.9 (6H, br. s.), 2.7-2.7 (1H, m), 2.6 (1H,d, J=13.4 Hz), 2.4 (1H, dd, J=11.6, 8.2 Hz), 2.1 (1H, dd, J=17.2, 6.3Hz), 2.0-2.1 (1H, m), 1.8-1.9 (1H, m), 1.8 (1H, d, J=12.8 Hz), 1.7 (3H,s), 1.7 (1H, d, J=6.7 Hz), 1.6-1.7 (1H, m), 1.5-1.6 (2H, m), 1.5 (4H, d,J=2.7 Hz), 1.3-1.4 (5H, m), 1.2-1.3 (1H, m), 1.1 (3H, s), 1.0-1.1 (2H,m), 1.0 (3H, s), 1.0-1.0 (3H, m), 0.9 (6H, s). ¹³C NMR (CHLOROFORM-d) δppm 14.2, 15.8, 16.3, 18.4, 19.2, 19.5, 20.7, 21.1, 25.0, 27.1, 29.1,29.5, 29.6, 33.3, 35.3, 35.4, 36.0, 37.2, 37.3, 40.3, 41.4, 41.7, 43.4,46.7, 49.3, 51.7, 52.6, 53.4, 58.9, 63.9, 77.3, 109.8, 123.9, 127.6,128.2, 129.8, 145.9, 148.5, 149.4, 157.5, 167.0.

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a cloudy solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.255 g, 0.388 mmol) in THF (5 mL) was added a solution of lithiumhydroxide monohydrate (0.049 g, 1.16 mmol) in water (1.00 mL). Thereaction mixture was heated to 75° C. for 18 h. Then, the reaction wastreated with 1N HCl (1 mL) and concentrated in vacuo, absorbed ontosilica gel (3.5 g), loaded onto a silica gel column (12 g cartridge) andeluted with 90:10 DCM:MeOH to give the title compound (237 mg, 0.368mmol, 95% yield) as a white solid. LCMS: m/e 644.4 (M+H)⁺, 3.95 min(method 8). ¹H NMR (500 MHz, MeOD) δ ppm 7.9 (2H, d, J=8.2 Hz), 7.2 (2H,d, J=8.2 Hz), 5.9 (1H, s), 5.3-5.3 (1H, m), 4.8 (1H, d, J=1.8 Hz), 4.6(1H, s), 3.7-3.8 (1H, m), 3.4-3.6 (2H, m), 3.4 (1H, s), 3.2-3.3 (2H, m),2.9 (6H, s), 2.7 (1H, td, J=11.1, 5.0 Hz), 2.6 (1H, dd, J=10.2, 3.2 Hz),2.4 (1H, dd, J=12.1, 8.1 Hz), 2.2 (1H, dd, J=17.4, 6.4 Hz), 1.9-2.0 (2H,m), 1.8 (1H, d, J=13.4 Hz), 1.7 (3H, s), 1.7 (1H, br. s.), 1.7-1.7 (1H,m), 1.6-1.6 (2H, m), 1.5-1.6 (4H, m), 1.4-1.4 (5H, m), 1.3-1.4 (3H, m),1.2 (3H, s), 1.1-1.1 (1H, m), 1.0-1.1 (6H, m), 1.0 (3H, s), 1.0 (3H, s).¹³C NMR (MeOD) δ ppm 14.5, 16.3, 16.8, 19.2, 20.6, 21.3, 22.2, 26.3,28.2, 29.7, 30.4, 30.5, 34.5, 36.2, 36.4, 37.1, 38.2, 38.4, 41.5, 42.6,42.8, 43.6, 48.1, 49.0, 49.3, 49.3, 50.4, 50.6, 54.0, 55.6, 59.9, 64.9,110.3, 111.1, 124.8, 129.3, 130.7, 147.5, 150.9, 160.4.

Example 4 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(1-carboxycyclopropyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 25% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 1-aminocyclopropane-1-carboxylic acid ethyl esterhydrochloride was used instead of N,N-dimethylethylenediamine in Step 1.LCMS: m/e 657.3 (M+H)⁺, 4.18 min (method 8). ¹H NMR (500 MHz, MeOD) δppm 7.9 (2H, d, J=8.2 Hz), 7.2 (2H, d, J=8.2 Hz), 5.3-5.3 (1H, m), 4.8(1H, br. s.), 4.6 (1H, br. s.), 3.7-3.8 (1H, m), 3.6-3.6 (1H, m),3.5-3.6 (1H, m), 2.5-2.7 (2H, m), 2.4 (1H, dd, J=12.1, 8.4 Hz), 2.2 (1H,dd, J=17.1, 6.4 Hz), 2.0 (1H, d, J=11.9 Hz), 1.9 (2H, dt, J=6.6, 3.2Hz), 1.8-1.9 (2H, m), 1.7-1.8 (4H, m), 1.4-1.7 (7H, m), 1.4 (3H, td,J=13.1, 4.0 Hz), 1.3 (3H, t, J=11.7 Hz), 1.2 (3H, s), 1.1-1.1 (3H, m),1.1 (3H, d, J=2.4 Hz), 1.0 (3H, s), 1.0 (2H, s), 0.9 (1H, m).

Example 5 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(2-methyl-1-morpholinopropan-2-yl)ureido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 16% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-methyl-2-morpholinopropan-1-amine was used instead ofN,N-dimethylethylenediamine in Step 1. LCMS: m/e 714.3 (M+H)⁺, 3.97 min(method 8). ¹H NMR (500 MHz, MeOD) δ ppm 7.9 (2H, d, J=8.2 Hz), 7.2 (2H,d, J=8.2 Hz), 5.3 (1H, d, J=4.6 Hz), 4.7 (1H, br. s.), 2.5-2.7 (1H, m),2.2 (1H, dd, J=16.9, 6.0 Hz), 2.1 (1H, dd, J=13.3, 9.9 Hz), 1.9-2.0 (2H,m), 1.8-1.9 (3H, m), 1.8 (3H, br. s.), 1.7-1.8 (1H, m), 1.6-1.7 (5H, m),1.5-1.6 (3H, m), 1.4 (2H, d, J=13.4 Hz), 1.3-1.4 (1H, m), 1.2 (3H, br.s.), 1.1 (3H, br. s.), 1.1 (3H, br. s.), 1.0 (3H, br. s.), 1.0 (3H, br.s.).

Example 6 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(2-methyl-2-morpholinopropyl)ureido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 20% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-methyl-2-morpholinopropan-1-amine was used instead ofN,N-dimethylethylenediamine in Step 1. LCMS: m/e 714.3 (M+H)⁺, 3.95 min(method 8). ¹H NMR (500 MHz, MeOD) δ ppm 7.9 (2H, d, J=8.2 Hz), 7.2 (2H,d, J=8.2 Hz), 5.3 (1H, d, J=6.1 Hz), 4.8 (1H, s), 4.7 (1H, s), 4.1 (2H,d, J=12.2 Hz), 3.7-3.9 (2H, m), 3.5-3.6 (2H, m), 3.4-3.5 (2H, m), 3.2(2H, t, J=11.9 Hz), 2.6-2.7 (2H, m), 2.4 (1H, dd, J=12.1, 8.4 Hz), 2.2(1H, dd, J=17.1, 6.1 Hz), 2.0 (1H, t, J=10.8 Hz), 1.8-1.9 (1H, m), 1.8(1H, br. s.), 1.7 (3H, s), 1.7 (1H, td, J=13.3, 3.4 Hz), 1.6-1.6 (2H,m), 1.5-1.6 (4H, m), 1.4-1.5 (3H, m), 1.4-1.4 (6H, m), 1.3 (1H, d, J=9.5Hz), 1.1 (3H, s), 1.1 (3H, br. s.), 1.1 (3H, br. s.), 1.0 (3H, s), 1.0(3H, s).

Example 7 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(1-((diethylamino)methyl)cyclopropyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 25% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 1-((diethylamino)methyl)cyclopropanamine, 2 HCl was usedinstead of N,N-dimethylethylenediamine in Step 1. LCMS: m/e 698.3(M+H)⁺, 3.97 min (method 8). ¹H NMR (500 MHz, MeOD) δ ppm 7.9-8.0 (2H,m), 7.2-7.3 (2H, m), 5.3 (1H, dd, J=4.0, 1.8 Hz), 4.8 (1H, br. s.), 4.7(1H, br. s.), 3.2-3.3 (4H, m), 2.6 (1H, d, J=12.8 Hz), 2.5-2.6 (1H, m),2.3-2.4 (1H, m), 2.2 (1H, dd, J=16.0, 5.3 Hz), 1.9-2.0 (1H, m), 1.7-1.8(3H, m), 1.7 (3H, br. s.), 1.6-1.7 (4H, m), 1.5 (4H, d, J=7.3 Hz),1.4-1.5 (2H, m), 1.4 (8H, dd, J=7.0, 5.2 Hz), 1.3 (2H, br. s.), 1.1-1.2(1H, m), 1.1 (3H, br. s.), 1.1 (6H, br. s.), 1.0 (3H, d, J=1.5 Hz), 1.0(3H, br. s.), 0.9 (3H, br. s.).

Example 8 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(1-(piperidin-1-ylmethyl)cyclopropyl)ureido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 1-(piperidin-1-ylmethyl)cyclopropanamine, 2 HCl was usedinstead of N,N-dimethylethylenediamine in Step 1. LCMS: m/e 710.6(M+H)⁺, 2.00 min (method 6). ¹H NMR (500 MHz, MeOD) δ ppm 7.9 (2H, d,J=7.9 Hz), 7.2 (2H, d, J=7.9 Hz), 5.3 (1H, d, J=4.9 Hz), 4.8 (1H, s),4.7 (1H, s), 3.5-3.7 (2H, m), 3.3 (1H, s), 3.2-3.3 (2H, m), 3.0 (2H,ddd, J=12.0, 8.5, 3.7 Hz), 2.6 (1H, d, J=13.4 Hz), 2.6 (1H, td, J=10.9,5.0 Hz), 2.4 (1H, dd, J=11.9, 8.2 Hz), 2.2 (1H, dd, J=17.1, 6.4 Hz),1.9-2.1 (3H, m), 1.7-1.9 (5H, m), 1.7 (3H, s), 1.7-1.7 (1H, m), 1.5-1.7(8H, m), 1.3-1.5 (6H, m), 1.2-1.2 (1H, m), 1.1 (1H, d, J=4.0 Hz), 1.1(3H, s), 1.1 (6H, br. s.), 1.0 (3H, s), 1.0 (3H, s), 0.9-0.9 (2H, m).

Example 9 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-((3S,4S)-4-(dimethylamino)tetrahydrofuran-3-yl)piperazine-1-carboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 20% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except(3S,4S)—N,N-dimethyl-4-(piperazin-1-yl)tetrahydrofuran-3-amine was usedinstead of N,N-dimethylethylenediamine in Step 1. LCMS: m/e 755.6(M+H)⁺, 1.85 min (method 6). ¹H NMR (500 MHz, METHANOL-d₄) δ=7.93 (d,J=8.2 Hz, 2H), 7.23 (d, J=8.2 Hz, 2H), 5.31 (d, J=6.1 Hz, 1H), 4.78 (s,1H), 4.64 (br. s., 1H), 4.09 (d, J=3.4 Hz, 1H), 4.05 (d, J=4.9 Hz, 2H),4.02 (td, J=3.5, 6.8 Hz, 1H), 3.96 (td, J=5.1, 10.1 Hz, 1H), 3.73 (d,J=5.2 Hz, 1H), 3.56-3.41 (m, 4H), 2.96 (s, 6H), 2.87-2.66 (m, 5H), 2.59(d, J=13.1 Hz, 1H), 2.45 (dd, J=8.7, 11.7 Hz, 1H), 2.16 (dd, J=6.4, 17.1Hz, 1H), 1.97-1.90 (m, 1H), 1.90-1.82 (m, 1H), 1.82-1.74 (m, 2H), 1.73(s, 3H), 1.66-1.54 (m, 3H), 1.51 (d, J=12.5 Hz, 4H), 1.45-1.26 (m, 6H),1.23-1.15 (m, 2H), 1.13 (s, 3H), 1.10 (d, J=13.4 Hz, 2H), 1.06 (s, 3H),1.04 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H).

General Procedure for C-17 Urea Formation:

Step 1: General Procedure for the Preparation of C-17 Urea Methyl Esters

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatein THF (approximately 0.1 M) was added Hunig's base (3-9 equiv.) and theamine (3 equiv.). The mixture was stirred at rt for 2-72 h. The reactionmixture was concentrated and redissolved in a mixture of THF andmethanol and often a couple drops of water were added. The mixture wasfiltered and purified by reverse phase preparative HPLC.

Step 2: General Procedures for Hydrolysis of the Benzoic Ester UsingNaOH or LiOH.H₂O

The C-17 urea formed in Step 1 above was dissolved in either 1,4-dioxaneor THF to give approximately a 0.1M solution. Aqueous 1N NaOH (4 eq.)was added to the mixture and it was heated to 50-85° C. After heatingfor 2-48 h, the mixture was cooled to rt. The crude mixture was purifiedby reverse phase preparative HPLC.

Alternatively, the ester hydrolysis can be carried out as follows: TheC-17 urea formed in Step 1 above was dissolved in either 1,4-dioxane orTHF to give approximately a 0.1M solution. To the solution was addedwater (ratio 4:1 or 5:1 organic 1,4-dioxane or THF:water) followed byLiOH.H₂O (5-12 equiv.). The mixture was heated to 50-85° C. Afterheating for as little as 60 seconds to as long as 24 h, the mixture wascooled to rt. The crude mixture was purified by reverse phasepreparative HPLC.

Example 10 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(3-(dimethylamino)propyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using N1,N1-dimethylpropane-1,3-diamine as the reactantamine. The mono-TFA salt product was isolated after reverse phasepreparative HPLC purification as a white solid (60 mg, 32.7% yield).LCMS: m/z 658 (M+H⁺), retention time 1.86 min (method 2). ¹H NMR (500MHz, MeOD) δ ppm 0.97 (s, 3H), 0.99 (s, 3H), 1.07 (s, 6H), 1.11-1.13 (m,1H), 1.15 (s, 3H), 1.17-1.22 (m, 1H), 1.28-1.48 (m, 5H), 1.48-1.64 (m,6H), 1.64-1.83 (m, 7H), 1.83-2.01 (m, 4H), 2.18 (dd, J=17.09, 6.41 Hz,1H), 2.37 (dd, J=12.21, 8.24 Hz, 1H), 2.58-2.68 (m, 2H), 2.90 (s, 6H),3.13 (td, J=7.02, 1.83 Hz, 2H), 3.25 (td, J=6.49, 0.76 Hz, 1H), 4.66 (s,1H), 4.78 (d, J=1.53 Hz, 1H), 5.33 (dd, J=6.10, 1.22 Hz, 1H), 7.25 (m,J=8.24 Hz, 2H), 7.95 (m, J=8.24 Hz, 2H).

Example 11 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(3-morpholinopropyl)ureido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 3-morpholinopropan-1-amine as the reactant amine. Themono-TFA salt product was isolated after reverse phase preparative HPLCpurification as a white solid (85 mg, 43% yield). LCMS: m/z 700 (M+H⁺),retention time 1.89 min (method 2). ¹H NMR (500 MHz, MeOD) δ ppm 0.97(s, 3H), 0.99 (s, 3H), 1.07 (s, 6H), 1.11-1.13 (m, 1H), 1.15 (s, 3H),1.17-1.21 (m, 1H), 1.28-1.47 (m, 5H), 1.50-1.63 (m, 6H), 1.64-1.72 (m,1H), 1.74 (br. s., 1H), 1.75 (s, 3H), 1.76-1.83 (m, 2H), 1.87 (td,J=12.21, 3.36 Hz, 1H), 1.91-1.99 (m, 3H), 2.18 (dd, J=17.09, 6.41 Hz,1H), 2.35 (dd, J=12.05, 8.09 Hz, 1H), 2.58-2.67 (m, 2H), 3.11-3.20 (m,4H), 3.25-3.31 (m, 2H), 3.45 (t, J=12.97 Hz, 2H), 3.81 (t, J=12.51 Hz,2H), 4.11 (d, J=12.82 Hz, 2H), 4.66 (s, 1H), 4.78 (s, 1H), 5.33 (dd,J=6.10, 1.83 Hz, 1H), 7.24 (m, J=8.55 Hz, 2H), 7.95 (m, J=8.55 Hz, 2H).

Example 12 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(3-(2-methyl-1H-imidazol-1-yl)propyl)ureido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 3-(2-methyl-1H-imidazol-1-yl)propan-1-aminedihydrochloride as the reactant amine. The mono-TFA salt product wasisolated after reverse phase preparative HPLC purification as a whitesolid (40 mg, 21% yield). LCMS: m/z 709 (M+H⁺), retention time 1.83 min(method 2). ¹H NMR (500 MHz, MeOD) δ ppm 0.97 (s, 3H), 0.99 (s, 3H),1.07 (s, 6H), 1.12 (d, J=13.43 Hz, 1H), 1.15 (s, 3H), 1.17-1.22 (m, 1H),1.27-1.46 (m, 5H), 1.47-1.64 (m, 6H), 1.66-1.82 (m, 7H), 1.83-1.98 (m,2H), 2.04 (quin, J=6.94 Hz, 2H), 2.18 (dd, J=17.09, 6.41 Hz, 1H), 2.38(dd, J=12.36, 8.09 Hz, 1H), 2.58-2.65 (m, 2H), 2.66 (s, 3H), 3.18 (t,J=6.71 Hz, 2H), 4.18 (t, J=7.17 Hz, 2H), 4.66 (s, 1H), 4.78 (d, J=1.83Hz, 1H), 5.33 (dd, J=6.26, 1.68 Hz, 1H), 7.24 (m, J=8.55 Hz, 2H), 7.47(d, J=1.83 Hz, 1H), 7.59 (d, J=2.14 Hz, 1H), 7.95 (m, J=8.24 Hz, 2H).

Example 13 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(1H-imidazol-4-yl)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using histamine as the reactant amine. The mono-TFA saltproduct was isolated after reverse phase preparative HPLC purificationas a white solid (23 mg, 11% yield). LCMS: m/z 667 (M+H⁺), retentiontime 1.79 min (method 2). ¹H NMR (500 MHz, MeOD) δ ppm 0.97 (s, 3H),0.99 (s, 3H), 1.05 (s, 3H), 1.06 (s, 3H), 1.07-1.11 (m, 1H), 1.12 (s,3H), 1.13-1.20 (m, 1H), 1.26-1.45 (m, 5H), 1.49-1.68 (m, 7H), 1.71 (d,J=11.60 Hz, 1H), 1.74 (s, 3H), 1.75-1.94 (m, 4H), 2.17 (dd, J=17.09,6.41 Hz, 1H), 2.31 (dd, J=12.36, 8.09 Hz, 1H), 2.54-2.64 (m, 2H), 2.90(t, J=6.71 Hz, 2H), 3.45 (t, J=6.87 Hz, 2H), 4.65 (s, 1H), 4.76 (d,J=1.83 Hz, 1H), 5.33 (dd, J=6.10, 1.83 Hz, 1H), 7.24 (d, J=8.24 Hz, 2H),7.34 (s, 1H), 7.94 (d, J=8.24 Hz, 2H), 8.84 (d, J=1.22 Hz, 1H).

Example 14 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(3-(1H-imidazol-1-yl)propyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 3-(1H-imidazol-1-yl)propan-1-amine as the reactantamine. The mono-TFA salt product was isolated after reverse phasepreparative HPLC purification as a white solid (109 mg, 53% yield).LCMS: m/z 681 (M+H⁺), retention time 1.82 min (method 2). ¹H NMR (500MHz, MeOD) δ ppm 0.97 (s, 3H), 0.99 (s, 3H), 1.06 (s, 6H), 1.09-1.14 (m,1H), 1.15 (s, 3H), 1.17-1.21 (m, 1H), 1.27-1.46 (m, 5H), 1.47-1.63 (m,6H), 1.64-1.73 (m, 2H), 1.75 (s, 3H), 1.76-1.82 (m, 2H), 1.83-2.00 (m,2H), 2.07 (qd, J=7.07, 6.87 Hz, 2H), 2.18 (dd, J=17.09, 6.41 Hz, 1H),2.39 (dd, J=12.36, 8.09 Hz, 1H), 2.58-2.68 (m, 2H), 3.11-3.23 (m, 2H),4.31 (t, J=6.87 Hz, 2H), 4.66 (s, 1H), 4.78 (d, J=1.83 Hz, 1H), 5.33(dd, J=6.10, 1.83 Hz, 1H), 7.24 (m, J=8.54 Hz, 2H), 7.60 (t, J=1.53 Hz,1H), 7.71 (t, J=1.68 Hz, 1H), 7.94 (m, J=8.54 Hz, 2H), 9.00 (s, 1H).

Example 15 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(piperidine-1-carboxamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using piperidine as the reactant amine. The product wasisolated after reverse phase preparative HPLC purification as a whitesolid (10 mg, 6% yield). LCMS: m/z 641 (M+H⁺), retention time 2.67 min(method 2). ¹H NMR (500 MHz, MeOD) δ ppm 0.97 (s, 3H), 0.99 (s, 3H),1.07 (s, 3H), 1.08 (s, 3H), 1.12 (dt, J=13.81, 3.17 Hz, 1H), 1.16 (s,3H), 1.17-1.22 (m, 1H), 1.28-1.47 (m, 5H), 1.48-1.65 (m, 11H), 1.65-1.70(m, 2H), 1.71-1.90 (m, 7H), 1.91-2.02 (m, 1H), 2.14-2.21 (m, 1H), 2.49(dd, J=12.36, 8.09 Hz, 1H), 2.59-2.71 (m, 2H), 3.35-3.48 (m, 4H),4.63-4.67 (m, 1H), 4.80 (d, J=1.83 Hz, 1H), 5.33 (dd, J=6.10, 1.83 Hz,1H), 7.25 (m, J=8.24 Hz, 2H), 7.94 (m, J=8.24 Hz, 2H).

Example 16 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(carboxymethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using glycine methyl ester hydrochloride as the reactantamine. The product was isolated after reverse phase preparative HPLCpurification as a white solid (59 mg, 45% yield). LCMS: m/z 631 (M+H⁺),retention time 2.17 min (method 2). ¹H NMR (500 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm 0.94 (s, 3H), 0.95 (s, 3H), 1.02 (s,6H), 1.04-1.11 (m, 2H), 1.12 (s, 3H), 1.23-1.41 (m, 5H), 1.42-1.61 (m,6H), 1.65 (t, J=11.60 Hz, 1H), 1.68-1.79 (m, 6H), 1.85 (td, J=12.21,3.36 Hz, 1H), 1.92-2.05 (m, 1H), 2.13 (dd, J=17.09, 6.41 Hz, 1H), 2.36(dd, J=12.36, 8.09 Hz, 1H), 2.55-2.66 (m, 2H), 3.80-3.95 (m, 2H),4.58-4.64 (m, 1H), 4.74 (d, J=1.83 Hz, 2H), 5.29 (dd, J=6.26, 1.68 Hz,1H), 7.19-7.23 (m, 2H), 7.91-7.95 (m, 2H).

Example 17 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-((S)-1-carboxyethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using L-alanine methyl ester hydrochloride as the reactantamine. The product was isolated after reverse phase preparative HPLCpurification as a white solid (74 mg, 54% yield). LCMS: m/z 645 (M+H⁺),retention time 2.26 min (method 2). ¹H NMR (500 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm 0.93 (br. s., 3H), 0.94 (br. s., 3H),0.99 (s, 6H), 1.02-1.09 (m, 2H), 1.10 (s, 3H), 1.19-1.35 (m, 5H), 1.37(d, J=7.32 Hz, 3H), 1.39-1.57 (m, 6H), 1.63 (t, J=11.60 Hz, 1H),1.66-1.76 (m, 6H), 1.76-1.85 (m, 1H), 1.88-1.99 (m, 1H), 2.11 (dd,J=17.09, 6.41 Hz, 1H), 2.35 (dd, J=12.36, 8.09 Hz, 1H), 2.50-2.61 (m,2H), 4.28 (q, J=7.02 Hz, 1H), 4.61 (br. s., 1H), 4.72 (br. s., 1H),5.26-5.31 (m, 1H), 7.20 (d, J=8.24 Hz, 2H), 7.92 (d, J=8.55 Hz, 2H).

Example 18 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-((S)-1-carboxy-2-hydroxyethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using L-serine methyl ester hydrochloride as the reactantamine. The product was isolated after reverse phase preparative HPLCpurification as a white solid (70 mg, 48% yield). LCMS: m/z 661 (M+H⁺),retention time 2.19 min (method 2). ¹H NMR (500 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm 0.93 (br. s., 3H), 0.93 (s, 3H), 0.99(br. s., 3H), 1.00 (s, 3H), 1.03-1.09 (m, 2H), 1.11 (s, 3H), 1.21-1.41(m, 5H), 1.41-1.57 (m, 6H), 1.64 (t, J=11.60 Hz, 1H), 1.67-1.77 (m, 6H),1.84 (td, J=12.21, 3.36 Hz, 1H), 1.88-1.99 (m, 1H), 2.11 (dd, J=17.09,6.41 Hz, 1H), 2.35 (dd, J=12.21, 8.24 Hz, 1H), 2.54-2.63 (m, 2H), 3.80(dd, J=10.99, 3.66 Hz, 1H), 3.93 (dd, J=10.99, 4.27 Hz, 1H), 4.37 (t,J=3.97 Hz, 1H), 4.61 (br. s., 1H), 4.72 (d, J=1.53 Hz, 1H), 5.28 (dd,J=6.26, 1.68 Hz, 1H), 7.20 (m, J=8.54 Hz, 2H), 7.92 (m, J=8.24 Hz, 2H).

Example 19 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-((R)-1-carboxyethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using D-alanine methyl ester hydrochloride as the reactantamine. The product was isolated after reverse phase preparative HPLCpurification as a white solid (68 mg, 50% yield). LCMS: m/z 645 (M+H⁺),retention time 2.23 min (method 2). ¹H NMR (500 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm 0.93 (br. s., 3H), 0.94 (br. s., 3H),1.00 (s, 6H), 1.03-1.14 (m, 5H), 1.20-1.36 (m, 5H), 1.37 (d, J=7.02 Hz,3H), 1.40-1.58 (m, 6H), 1.58-1.68 (m, 2H), 1.68-1.75 (m, 5H), 1.75-1.83(m, 1H), 1.92-2.03 (m, 1H), 2.11 (dd, J=17.09, 6.41 Hz, 1H), 2.34 (dd,J=12.21, 8.24 Hz, 1H), 2.51-2.60 (m, 2H), 4.27 (q, J=7.32 Hz, 1H), 4.60(br. s., 2H), 4.72 (d, J=1.53 Hz, 1H), 5.28 (dd, J=6.10, 1.53 Hz, 1H),7.20 (m, J=8.55 Hz, 2H), 7.92 (m, J=8.24 Hz, 2H).

Example 20 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-((R)-1-carboxy-2-hydroxyethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using D-serine methyl ester hydrochloride as the reactantamine. The product was isolated after reverse phase preparative HPLCpurification as a white solid (51 mg, 34% yield). LCMS: m/z 661 (M+H⁺),retention time 2.11 min (method 2). ¹H NMR (500 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm 0.92 (br. s., 6H), 0.98 (br. s., 6H),1.02-1.14 (m, 5H), 1.17-1.38 (m, 5H), 1.39-1.58 (m, 6H), 1.58-1.75 (m,7H), 1.76-1.86 (m, 1H), 1.90-2.04 (m, 1H), 2.04-2.13 (m, 1H), 2.36 (t,J=9.77 Hz, 1H), 2.56 (d, J=12.51 Hz, 2H), 3.81 (d, J=10.99 Hz, 1H), 3.94(d, J=10.99 Hz, 1H), 4.35 (d, J=2.44 Hz, 1H), 4.60 (br. s., 1H), 4.71(br. s., 1H), 5.28 (br. s., 1H), 7.19 (m, J=7.32 Hz, 2H), 7.92 (m,J=7.63 Hz, 2H).

Example 21 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)carbamoyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 4-(2-aminoethyl)thiomorpholine 1,1-dioxide as thereactant amine. The mono-TFA salt product was isolated after reversephase preparative HPLC purification as a white solid (121 mg, 74%yield). LCMS: m/z 734 (M+H⁺), retention time 2.49 min (method 11). ¹HNMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.94 (s,3H), 0.95 (s, 3H), 1.02 (br. s., 3H), 1.03 (br. s., 3H), 1.10 (s, 3H),1.11-1.17 (m, 2H), 1.21-1.60 (m, 11H), 1.63-1.82 (m, 8H), 1.86-2.00 (m,1H), 2.13 (dd, J=17.24, 6.26 Hz, 1H), 2.35 (dd, J=12.05, 8.39 Hz, 1H),2.52-2.63 (m, 2H), 3.20 (br. s., 2H), 3.39-3.52 (m, 6H), 3.69 (br. s.,4H), 4.63 (s, 1H), 4.75 (d, J=1.22 Hz, 1H), 5.29 (d, J=4.58 Hz, 1H),7.21 (m, J=8.24 Hz, 2H), 7.93 (m, J=8.24 Hz, 2H).

Example 22 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-dioxido-4-thiomorpholinyl)propyl)carbamoyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 4-(3-aminopropyl)thiomorpholine 1,1-dioxide as thereactant amine. The mono-TFA salt product was isolated after reversephase preparative HPLC purification as a white solid (115 mg, 59%yield). LCMS: m/z 748 (M+H⁺), retention time 2.44 min (method 11). ¹HNMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.95 (s,3H), 0.96 (s, 3H), 1.02 (br. s., 3H), 1.03 (br. s., 3H), 1.11 (s, 3H),1.12-1.18 (m, 2H), 1.24-1.44 (m, 5H), 1.44-1.60 (m, 6H), 1.63-1.80 (m,8H), 1.85-1.99 (m, 3H), 2.14 (dd, J=17.09, 6.41 Hz, 1H), 2.32 (dd,J=12.05, 8.09 Hz, 1H), 2.52-2.63 (m, 2H), 3.14 (t, J=7.02 Hz, 2H),3.19-3.30 (m, 2H), 3.50 (d, J=4.58 Hz, 4H), 3.65 (d, J=5.19 Hz, 4H),4.63 (s, 1H), 4.75 (s, 1H), 5.27-5.32 (m, 1H), 7.21 (m, J=8.24 Hz, 2H),7.93 (m, J=8.24 Hz, 2H).

Example 23 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-((2-hydroxyethyl)(methyl)amino)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 2-((2-aminoethyl)(methyl)amino)ethanol as the reactantamine. The mono-TFA salt product was isolated after reverse phasepreparative HPLC purification as a white solid (43 mg, 69% yield). LCMS:m/z 674 (M+H⁺), retention time 2.41 min (method 11). ¹H NMR (500 MHz,1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.93 (br. s., 3H), 0.94(br. s., 3H), 1.00 (br. s., 3H), 1.00 (br. s., 3H), 1.08 (s, 3H),1.08-1.15 (m, 2H), 1.22-1.39 (m, 5H), 1.40-1.56 (m, 6H), 1.59-1.79 (m,8H), 1.85-1.99 (m, 1H), 2.11 (dd, J=17.09, 6.41 Hz, 1H), 2.35 (br. s.,1H), 2.48-2.61 (m, 2H), 2.96 (s, 3H), 3.09-3.61 (m, 6H), 3.87 (t, J=5.19Hz, 2H), 4.61 (br. s., 1H), 4.73 (br. s., 1H), 5.24-5.31 (m, 1H), 7.20(d, J=8.24 Hz, 2H), 7.92 (d, J=8.24 Hz, 2H).

Example 24 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)-3-methylureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using N1,N1,N2-trimethylethane-1,2-diamine as the reactantamine. The mono-TFA salt product was isolated after reverse phasepreparative HPLC purification as a white solid (34 mg, 57% yield). LCMS:m/z 658 (M+H⁺), retention time 2.41 min (method 11). ¹H NMR (500 MHz,1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.93 (br. s., 3H), 0.94(br. s., 3H), 1.00 (s, 3H), 1.03 (s, 3H), 1.10 (s, 3H), 1.10-1.20 (m,2H), 1.20-1.28 (m, 1H), 1.31-1.42 (m, 4H), 1.44-1.58 (m, 7H), 1.62-1.80(m, 7H), 1.88-2.01 (m, 1H), 2.12 (dd, J=17.09, 6.10 Hz, 1H), 2.41-2.56(m, 3H), 2.92 (s, 6H), 3.03 (s, 3H), 3.18-3.31 (m, 2H), 3.51 (ddd,J=15.11, 5.95, 5.80 Hz, 1H), 3.73-3.83 (m, 1H), 4.54 (s, 1H), 4.64 (br.s., 1H), 4.75 (s, 1H), 5.25-5.31 (m, 1H), 7.20 (d, J=8.24 Hz, 2H), 7.92(d, J=8.24 Hz, 2H).

Example 25 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(1H-imidazol-1-yl)ethyl)-3-methylureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 2-(1H-imidazol-1-yl)-N-methylethanamine, 2 HCl as thereactant amine. The mono-TFA salt product was isolated after reversephase preparative HPLC purification as a white solid (35 mg, 56% yield).LCMS: m/z 681 (M+H⁺), retention time 2.39 min (method 11). ¹H NMR (500MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.94 (br. s., 3H),0.94 (br. s., 3H), 1.00 (s, 3H), 1.02 (s, 3H), 1.09 (s, 3H), 1.09-1.19(m, 2H), 1.23-1.42 (m, 5H), 1.43-1.54 (m, 6H), 1.54-1.60 (m, 1H),1.61-1.76 (m, 7H), 1.80-1.94 (m, 1H), 2.12 (dd, J=17.24, 6.26 Hz, 1H),2.29 (dd, J=12.67, 8.09 Hz, 1H), 2.35-2.51 (m, 2H), 3.01 (s, 3H), 3.65(dt, J=14.57, 5.84 Hz, 1H), 3.79-3.89 (m, 1H), 4.33-4.43 (m, 2H), 4.64(br. s., 1H), 4.74 (br. s., 1H), 5.25-5.31 (m, 1H), 7.20 (d, J=8.55 Hz,2H), 7.41 (t, J=1.53 Hz, 1H), 7.51 (t, J=1.68 Hz, 1H), 7.92 (d, J=8.24Hz, 2H), 8.88 (d, J=1.22 Hz, 1H).

Example 26 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-acetamidoethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using N-(2-aminoethyl)acetamide as the reactant amine. Theproduct was isolated after reverse phase preparative HPLC purificationas a white solid (24 mg, 48% yield). LCMS: m/z 658 (M+H⁺), retentiontime 2.73 min (method 11). ¹H NMR (500 MHz, 1:1 mixture of CDCl3 andMeOD, MeOD lock) δ ppm 0.93 (br. s., 3H), 0.94 (br. s., 3H), 1.00 (br.s., 3H), 1.00 (br. s., 3H), 1.04-1.15 (m, 5H), 1.21-1.41 (m, 6H),1.41-1.58 (m, 6H), 1.58-1.67 (m, 2H), 1.70 (s, 3H), 1.70-1.82 (m, 3H),1.86-1.94 (m, 1H), 1.96 (s, 3H), 2.11 (dd, J=17.40, 6.41 Hz, 1H), 2.34(dd, J=12.05, 8.09 Hz, 1H), 2.49-2.61 (m, 2H), 3.19-3.27 (m, 4H), 4.61(br. s., 1H), 4.72 (s, 1H), 5.25-5.31 (m, 1H), 7.20 (d, J=8.55 Hz, 2H),7.92 (d, J=8.24 Hz, 2H).

Example 27 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(2-(2-oxopiperidin-1-yl)ethyl)ureido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 1-(2-aminoethyl)piperidin-2-one hydrobromide as thereactant amine. The product was isolated after reverse phase preparativeHPLC purification as a white solid (37 mg, 68% yield). LCMS: m/z 698(M+H⁺), retention time 2.83 min (method 11). ¹H NMR (500 MHz, 1:1mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.93 (br. s., 3H), 0.94 (br.s., 3H), 1.00 (s, 6H), 1.04-1.14 (m, 5H), 1.21-1.41 (m, 5H), 1.41-1.58(m, 6H), 1.58-1.67 (m, 2H), 1.70 (s, 3H), 1.70-1.85 (m, 7H), 1.86-1.97(m, 1H), 2.11 (dd, J=17.09, 6.10 Hz, 1H), 2.29-2.39 (m, 3H), 2.50-2.61(m, 2H), 3.30-3.32 (m, 1H), 3.40 (t, J=5.34 Hz, 2H), 3.45 (t, J=5.95 Hz,2H), 4.61 (br. s., 1H), 4.72 (br. s., 1H), 5.25-5.31 (m, 1H), 7.20 (d,J=8.24 Hz, 2H), 7.92 (d, J=8.24 Hz, 2H).

Example 28 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(2-(2-oxopyrrolidin-1-yl)ethyl)ureido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 1-(2-aminoethyl)pyrrolidin-2-one oxalic acid salt asthe reactant amine. The product was isolated after reverse phasepreparative HPLC purification as a white solid (37 mg, 67% yield). LCMS:m/z 684 (M+H⁺), retention time 2.78 min (method 11). ¹H NMR (500 MHz,1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.93 (s, 3H), 0.94 (s,3H), 1.00 (s, 6H), 1.04-1.15 (m, 5H), 1.21-1.41 (m, 6H), 1.41-1.59 (m,6H), 1.59-1.67 (m, 2H), 1.67-1.81 (m, 6H), 1.86-1.97 (m, 1H), 2.00-2.08(m, 2H), 2.11 (dd, J=17.09, 6.41 Hz, 1H), 2.33 (dd, J=12.36, 8.09 Hz,1H), 2.38 (t, J=8.09 Hz, 2H), 2.50-2.60 (m, 2H), 3.28-3.32 (m, 2H), 3.53(t, J=7.32 Hz, 2H), 4.61 (s, 1H), 4.72 (d, J=1.53 Hz, 1H), 5.28 (dd,J=5.95, 1.68 Hz, 1H), 7.20 (m, J=8.54 Hz, 2H), 7.92 (m, J=8.24 Hz, 2H).

Example 29 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(3-(2-oxopyrrolidin-1-yl)propyl)ureido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 1-(3-aminopropyl)pyrrolidin-2-one as the reactantamine. The product was isolated after reverse phase preparative HPLCpurification as a white solid (38 mg, 69% yield). LCMS: m/z 698 (M+H⁺),retention time 2.79 min (method 11). ¹H NMR (500 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm 0.93 (br. s., 3H), 0.94 (br. s., 3H),1.00 (br. s., 3H), 1.00 (s, 3H), 1.04-1.16 (m, 5H), 1.21-1.41 (m, 5H),1.41-1.59 (m, 6H), 1.59-1.76 (m, 9H), 1.80 (td, J=12.21, 3.05 Hz, 1H),1.88-2.00 (m, 1H), 2.03-2.16 (m, 3H), 2.36 (dd, J=12.21, 8.24 Hz, 1H),2.42 (t, J=8.09 Hz, 2H), 2.51-2.64 (m, 2H), 3.09 (t, J=6.56 Hz, 2H),3.25-3.38 (m, 2H), 3.47 (t, J=7.17 Hz, 2H), 4.61 (s, 1H), 4.73 (d,J=1.53 Hz, 1H), 5.25-5.32 (m, 1H), 7.20 (m, J=8.24 Hz, 2H), 7.92 (m,J=8.24 Hz, 2H).

Example 30 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3,3-bis(3-(dimethylamino)propyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis usingN1-(3-(dimethylamino)propyl)-N3,N3-dimethylpropane-1,3-diamine as thereactant amine. The bis-TFA salt product was isolated after reversephase preparative HPLC purification as a white solid (15 mg, 20% yield).LCMS: m/z 743 (M+H⁺), retention time 2.27 min (method 11). ¹H NMR (500MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.94 (s, 3H), 0.94(s, 3H), 1.00 (s, 3H), 1.05 (s, 3H), 1.09 (s, 3H), 1.11-1.19 (m, 2H),1.26 (d, J=6.71 Hz, 1H), 1.30-1.44 (m, 3H), 1.44-1.62 (m, 8H), 1.63-1.81(m, 7H), 1.83-1.95 (m, 1H), 2.02 (br. s., 4H), 2.13 (dd, J=17.09, 6.41Hz, 1H), 2.41 (dd, J=12.51, 8.24 Hz, 1H), 2.51 (td, J=10.91, 5.04 Hz,1H), 2.59 (d, J=13.43 Hz, 1H), 2.89 (s, 12H), 3.13 (t, J=7.02 Hz, 4H),3.34-3.43 (m, 4H), 4.76 (s, 1H), 5.26-5.33 (m, 1H), 7.20 (m, J=8.55 Hz,2H), 7.92 (m, J=8.24 Hz, 2H).

Example 31 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)-2-oxoethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 2-amino-N,N-dimethylacetamide as the reactant amine.The product was isolated after reverse phase preparative HPLCpurification as a white solid (7 mg, 14% yield). LCMS: m/z 658 (M+H⁺),retention time 2.77 min (method 11). ¹H NMR (500 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm 0.93 (s, 3H), 0.94 (s, 3H), 1.01 (s,6H), 1.05-1.16 (m, 5H), 1.21-1.41 (m, 6H), 1.41-1.57 (m, 6H), 1.60-1.78(m, 7H), 1.84 (td, J=12.28, 3.51 Hz, 1H), 1.91-2.01 (m, 1H), 2.12 (dd,J=17.09, 6.41 Hz, 1H), 2.36 (dd, J=12.21, 7.93 Hz, 1H), 2.55-2.64 (m,2H), 2.98 (s, 3H), 3.03 (s, 3H), 3.89-4.07 (m, 2H), 4.61 (d, J=1.22 Hz,1H), 4.73 (d, J=1.83 Hz, 1H), 5.29 (dd, J=6.10, 1.83 Hz, 1H), 7.20 (d,J=8.54 Hz, 2H), 7.92 (d, J=8.24 Hz, 2H).

Example 32 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3,3-dimethylureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was formed as a byproduct during the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)-2-oxoethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid. Hydrolysis of the penultimate methyl ester by the generalprocedure as described and purification by reverse phase preparativeHPLC gave a white solid (13 mg, 29% yield). LCMS: m/z 601 (M+H⁺),retention time 2.90 min (method 11). ¹H NMR (500 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm 0.94 (s, 3H), 0.94 (s, 3H), 1.00 (s,3H), 1.03 (s, 3H), 1.10 (s, 3H), 1.11-1.19 (m, 2H), 1.24-1.44 (m, 6H),1.45-1.60 (m, 7H), 1.61-1.66 (m, 1H), 1.69 (d, J=5.49 Hz, 2H), 1.71 (s,3H), 1.72-1.78 (m, 2H), 1.91-2.01 (m, 1H), 2.12 (dd, J=17.09, 6.41 Hz,1H), 2.42-2.52 (m, 2H), 2.56 (dt, J=13.20, 3.32 Hz, 1H), 2.95 (s, 6H),4.63 (d, J=1.53 Hz, 1H), 4.74 (d, J=1.83 Hz, 1H), 5.29 (dd, J=6.26, 1.68Hz, 1H), 7.20 (m, J=8.24 Hz, 2H), 7.92 (m, J=8.24 Hz, 2H).

Example 33 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-carboxyethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using methyl-3-aminopropanoate HCl as the reactant amine. Theproduct was isolated after reverse phase preparative HPLC purificationas a white solid (33 mg, 67% yield). LCMS: m/z 645 (M+H⁺), retentiontime 2.69 min (method 11). ¹H NMR (500 MHz, 1:1 mixture of CDCl3 andMeOD, MeOD lock) δ ppm 0.93 (br. s., 3H), 0.94 (s, 3H), 1.00 (s, 6H),1.03-1.14 (m, 5H), 1.21-1.40 (m, 5H), 1.40-1.58 (m, 6H), 1.58-1.67 (m,2H), 1.67-1.75 (m, 5H), 1.75-1.83 (m, 1H), 1.87-1.98 (m, 1H), 2.11 (dd,J=17.09, 6.41 Hz, 1H), 2.34 (dd, J=12.05, 8.09 Hz, 1H), 2.49 (t, J=6.26Hz, 2H), 2.51-2.63 (m, 2H), 3.37 (td, J=6.33, 3.81 Hz, 2H), 4.60 (s,1H), 4.72 (d, J=1.83 Hz, 1H), 5.28 (dd, J=6.10, 1.53 Hz, 1H), 7.20 (m,J=8.54 Hz, 2H), 7.92 (m, J=8.24 Hz, 2H).

Example 34 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(4-methyl-1,4-diazepane-1-carboxamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 1-methyl-1,4-diazepane as the reactant amine. Themono-TFA salt product was isolated after reverse phase preparative HPLCpurification as a white solid (30 mg, 48% yield). LCMS: m/z 670 (M+H⁺),retention time 2.41 min (method 11). ¹H NMR (400 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm 0.94 (s, 6H), 1.00 (s, 3H), 1.04 (s,3H), 1.09 (s, 3H), 1.10-1.22 (m, 3H), 1.22-1.45 (m, 5H), 1.45-1.64 (m,8H), 1.64-1.81 (m, 7H), 1.87-2.01 (m, 1H), 2.12 (dd, J=17.19, 6.40 Hz,1H), 2.33 (br. s., 2H), 2.40-2.53 (m, 2H), 2.58 (d, J=13.30 Hz, 1H),2.92 (s, 3H), 3.54 (br. s., 2H), 4.64 (s, 1H), 4.75 (d, J=1.00 Hz, 1H),5.26-5.33 (m, 1H), 7.20 (m, J=8.28 Hz, 2H), 7.92 (m, J=8.28 Hz, 2H).

Example 35 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-acetyl-1,4-diazepane-1-carboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 1-[1,4-diazepan1-yl]ethanone as the reactant amine. Theproduct was isolated after reverse phase preparative HPLC purificationas a white solid (27 mg, 48% yield). LCMS: m/z 698 (M+H⁺), retentiontime 2.74 min (method 11). ¹H NMR (400 MHz, 1:1 mixture of CDCl3 andMeOD, MeOD lock) δ ppm 0.94 (br. s., 3H), 0.94 (br. s., 3H), 1.01 (s,3H), 1.03 (s, 3H), 1.09 (s, 3H), 1.10-1.19 (m, 2H), 1.21-1.66 (m, 14H),1.67-1.78 (m, 6H), 1.85-2.02 (m, 3H), 2.11 (s, 2H), 2.12-2.17 (m, 2H),2.34-2.50 (m, 2H), 2.54-2.64 (m, 1H), 3.41-3.48 (m, 2H), 3.50-3.64 (m,5H), 4.63 (br. s., 1H), 4.75 (d, J=9.16 Hz, 1H), 5.29 (d, J=4.58 Hz,1H), 7.20 (d, J=8.24 Hz, 2H), 7.92 (d, J=8.24 Hz, 2H).

Example 36 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(methoxycarbonylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was formed as a byproduct during the urea formationstep in the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-acetyl-1,4-diazepane-1-carboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid. Hydrolysis of the penultimate methyl ester by the generalprocedure as described and purification by reverse phase preparativeHPLC gave a white solid (6 mg, 13% yield). LCMS: m/z 588 (M+H⁺),retention time 3.07 min (method 11). ¹H NMR (500 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm 0.93 (s, 3H), 0.94 (s, 3H), 1.00 (s,3H), 1.01 (s, 3H), 1.09 (s, 3H), 1.09-1.16 (m, 2H), 1.23-1.27 (m, 1H),1.28-1.44 (m, 5H), 1.45-1.57 (m, 6H), 1.59-1.77 (m, 9H), 1.88-2.00 (m,1H), 2.12 (dd, J=17.09, 6.41 Hz, 1H), 2.28-2.39 (m, 1H), 2.45-2.58 (m,2H), 3.62 (br. s., 3H), 4.62 (d, J=1.53 Hz, 1H), 4.74 (d, J=1.83 Hz,1H), 5.29 (dd, J=6.26, 1.68 Hz, 1H), 7.20 (d, J=8.24 Hz, 2H), 7.92 (d,J=8.24 Hz, 2H).

Example 37 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-cyclopentyl-3-oxopiperazine-1-carboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 1-cyclopentylpiperazin-2-one, HCl, 0.5 H₂O as thereactant amine. The product was isolated after reverse phase preparativeHPLC purification as a white solid (18 mg, 28% yield). LCMS: m/z 724(M+H⁺), retention time 2.97 min (method 11). ¹H NMR (500 MHz, 1:1mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.93 (br. s., 3H), 0.94 (br.s., 3H), 1.00 (s, 3H), 1.03 (s, 3H), 1.09 (s, 3H), 1.11-1.19 (m, 2H),1.24 (d, J=8.85 Hz, 1H), 1.30-1.42 (m, 4H), 1.43-1.60 (m, 10H),1.62-1.67 (m, 2H), 1.67-1.80 (m, 9H), 1.82-1.90 (m, 2H), 1.90-2.00 (m,1H), 2.12 (dd, J=17.09, 6.41 Hz, 1H), 2.40-2.60 (m, 3H), 3.35-3.41 (m,2H), 3.53-3.68 (m, 2H), 3.94-4.04 (m, 1H), 4.04-4.13 (m, 1H), 4.63 (br.s., 1H), 4.75 (s, 1H), 4.90 (quin, J=8.47 Hz, 1H), 5.25-5.31 (m, 1H),5.34-5.38 (m, 1H), 7.20 (d, J=8.24 Hz, 2H), 7.92 (d, J=8.24 Hz, 2H).

Example 38 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-(2-hydroxyethyl)piperazine-1-carboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 2-(piperazin-1-yl)ethanol as the reactant amine. Themono-TFA salt product was isolated after reverse phase preparative HPLCpurification as a white solid (12 mg, 18% yield). LCMS: m/z 686 (M+H⁺),retention time 2.41 min (method 11). ¹H NMR (500 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm 0.94 (s, 3H), 0.94 (s, 3H), 1.00 (s,3H), 1.04 (s, 3H), 1.08 (s, 3H), 1.09-1.19 (m, 2H), 1.24-1.28 (m, 1H),1.32-1.43 (m, 4H), 1.44-1.59 (m, 7H), 1.67-1.80 (m, 7H), 1.86-1.98 (m,1H), 2.12 (dd, J=17.24, 6.26 Hz, 1H), 2.42 (dd, J=12.36, 8.09 Hz, 1H),2.53-2.65 (m, 2H), 3.23-3.29 (m, 3H), 3.92 (dd, J=5.95, 4.43 Hz, 2H),4.75 (d, J=1.53 Hz, 1H), 5.29 (dd, J=6.10, 1.83 Hz, 1H), 7.20 (m, J=8.24Hz, 2H), 7.92 (m, J=8.54 Hz, 2H).

Example 39 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-(2-(dimethylamino)ethyl)piperazine-1-carboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using N,N-dimethyl-2-(piperazin-1-yl)ethanamine as thereactant amine. The bis-TFA salt product was isolated after reversephase preparative HPLC purification as a white solid (15 mg, 19% yield).LCMS: m/z 713 (M+H⁺), retention time 2.44 min (method 11). ¹H NMR (500MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.94 (s, 3H), 0.94(s, 3H), 1.00 (s, 3H), 1.03 (s, 3H), 1.08 (s, 3H), 1.09-1.20 (m, 2H),1.24-1.44 (m, 7H), 1.44-1.62 (m, 7H), 1.64-1.79 (m, 7H), 1.88-2.00 (m,1H), 2.12 (dd, J=17.09, 6.41 Hz, 1H), 2.44 (dd, J=12.21, 8.24 Hz, 1H),2.51 (dt, J=10.15, 5.15 Hz, 1H), 2.57 (d, J=13.12 Hz, 1H), 2.73 (br. s.,4H), 2.87-2.99 (m, 8H), 3.39-3.55 (m, 4H), 4.75 (s, 1H), 5.29 (d, J=4.58Hz, 1H), 7.20 (m, J=8.24 Hz, 2H), 7.92 (m, J=8.24 Hz, 2H).

Example 40 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(4-(1-methylpiperidin-4-yl)piperazine-1-carboxamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 1-(1-methylpiperidin-4-yl)piperazine as the reactantamine. The bis-TFA salt product was isolated after reverse phasepreparative HPLC purification as a white solid (48 mg, 61% yield). LCMS:m/z 739 (M+H⁺), retention time 2.41 min (method 11). ¹H NMR (500 MHz,1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.93 (s, 3H), 0.94 (s,3H), 1.00 (s, 3H), 1.03 (s, 3H), 1.08 (s, 3H), 1.09-1.19 (m, 2H),1.23-1.28 (m, 1H), 1.29-1.44 (m, 4H), 1.44-1.64 (m, 9H), 1.65-1.79 (m,7H), 1.87-1.99 (m, 1H), 1.99-2.08 (m, 2H), 2.12 (dd, J=17.09, 6.41 Hz,1H), 2.40-2.60 (m, 3H), 2.77-2.93 (m, 5H), 3.03-3.13 (m, 1H), 3.35 (br.s., 4H), 3.47 (br. s., 4H), 3.99-4.15 (m, 2H), 4.63 (s, 1H), 4.75 (d,J=1.22 Hz, 1H), 5.29 (dd, J=6.10, 1.53 Hz, 1H), 7.20 (m, J=8.54 Hz, 2H),7.92 (m, J=8.24 Hz, 2H).

Example 41 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-acetylpiperazine-1-carboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 1-(piperazin-1-yl)ethanone as the reactant amine. Theproduct was isolated after reverse phase preparative HPLC purificationas a white solid (6 mg, 11% yield). LCMS: m/z 684 (M+H⁺), retention time2.81 min (method 11). ¹H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD,MeOD lock) δ ppm 0.94 (br. s., 3H), 0.94 (s, 3H), 1.01 (s, 3H), 1.04 (s,3H), 1.09 (s, 3H), 1.10-1.20 (m, 2H), 1.24-1.28 (m, 2H), 1.29-1.45 (m,4H), 1.45-1.62 (m, 7H), 1.64-1.79 (m, 7H), 1.89-2.00 (m, 1H), 2.08-2.16(m, 4H), 2.46 (dd, J=12.36, 8.09 Hz, 1H), 2.52 (td, J=10.60, 5.34 Hz,1H), 2.58 (ddd, J=13.35, 3.36, 3.13 Hz, 1H), 3.35-3.48 (m, 3H),3.49-3.60 (m, 3H), 3.60-3.73 (m, 2H), 4.75 (d, J=1.53 Hz, 1H), 5.29 (dd,J=6.10, 1.53 Hz, 1H), 7.20 (m, J=8.54 Hz, 2H), 7.92 (m, J=8.54 Hz, 2H).

Example 42 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(5-oxo-1,4-diazepane-1-carboxamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 1,4-diazepan-5-one as the reactant amine. The productwas isolated after reverse phase preparative HPLC purification as awhite solid (26 mg, 46% yield). LCMS: m/z 670 (M+H⁺), retention time2.70 min (method 11). ¹H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD,MeOD lock) δ ppm 0.94 (s, 3H), 0.94 (s, 3H), 1.01 (s, 3H), 1.04 (s, 3H),1.09 (s, 3H), 1.10-1.19 (m, 2H), 1.26 (dd, J=7.17, 3.20 Hz, 1H),1.31-1.43 (m, 5H), 1.45-1.54 (m, 6H), 1.55-1.60 (m, 2H), 1.63-1.80 (m,7H), 1.88-1.99 (m, 1H), 2.13 (dd, J=16.94, 6.26 Hz, 1H), 2.44-2.53 (m,2H), 2.60 (ddd, J=13.50, 2.82, 2.59 Hz, 1H), 2.68 (t, J=5.19 Hz, 2H),3.49-3.68 (m, 4H), 4.57 (s, 1H), 4.75 (d, J=1.53 Hz, 1H), 5.29 (dd,J=6.10, 1.53 Hz, 1H), 7.20 (d, J=8.54 Hz, 2H), 7.92 (d, J=8.54 Hz, 2H).

Example 43 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-aminoethyl)-3-(2-carboxyethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was formed as a byproduct during the ester hydrolysisstep in the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(5-oxo-1,4-diazepane-1-carboxamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid. Purification by reverse phase preparative HPLC gave a white solid(10 mg, 15% yield) mono-TFA salt. LCMS: m/z 688 (M+H⁺), retention time2.40 min (method 11). ¹H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD,MeOD lock) δ ppm 0.94 (s, 6H), 1.01 (s, 3H), 1.04 (s, 3H), 1.07-1.17 (m,5H), 1.23-1.42 (m, 7H), 1.44-1.62 (m, 7H), 1.67-1.81 (m, 6H), 1.84-2.00(m, 2H), 2.13 (dd, J=17.39, 6.41 Hz, 1H), 2.38 (dd, J=11.90, 7.93 Hz,1H), 2.51-2.58 (m, 1H), 2.59-2.66 (m, 1H), 2.66-2.73 (m, 1H), 2.77 (td,J=10.83, 4.58

Hz, 1H), 2.99-3.10 (m, 2H), 3.36-3.46 (m, 3H), 3.76 (ddd, J=15.56, 9.31,3.81 Hz, 1H), 4.76 (d, J=1.83 Hz, 1H), 5.29 (dd, J=6.10, 1.53 Hz, 1H),7.20 (m, J=8.24 Hz, 2H), 7.92 (m, J=8.24 Hz, 2H).

Example 44 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-methyl-3-(2-(pyrrolidin-1-yl)ethyl)ureido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using N-methyl-2-(pyrrolidin-1-yl)ethanamine as the reactantamine. The product was isolated after reverse phase preparative HPLCpurification as a white solid (34 mg, 54% yield) mono-TFA salt. LCMS:m/z 684 (M+H⁺), retention time 2.41 min (method 11). ¹H NMR (500 MHz,1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.94 (br. s., 3H), 0.94(br. s., 3H), 1.00 (s, 3H), 1.04 (s, 3H), 1.10 (s, 3H), 1.10-1.21 (m,2H), 1.26 (dd, J=10.68, 2.75 Hz, 1H), 1.32-1.43 (m, 4H), 1.45-1.59 (m,7H), 1.62-1.81 (m, 8H), 1.87-2.00 (m, 1H), 2.08 (br. s., 4H), 2.12 (dd,J=17.09, 6.41 Hz, 1H), 2.41-2.57 (m, 3H), 3.03 (s, 3H), 3.06 (br. s.,2H), 3.25-3.39 (m, 2H), 3.52 (dt, J=14.65, 6.26 Hz, 1H), 3.63-3.83 (m,3H), 4.64 (br. s., 1H), 4.75 (s, 1H), 5.26-5.32 (m, 1H), 7.20 (d, J=7.93Hz, 2H), 7.92 (d, J=8.24 Hz, 2H).

Example 45 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(piperazine-1-carboxamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 1-(piperazin-1-yl)ethanone as the reactant amine. Theproduct was isolated after reverse phase preparative HPLC purificationas a white solid (5 mg, 8% yield) mono-TFA salt. LCMS: m/z 642 (M+H⁺),retention time 2.42 min (method 11). ¹H NMR (500 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm 0.94 (s, 3H), 0.94 (s, 3H), 1.00 (s,3H), 1.04 (s, 3H), 1.08 (s, 3H), 1.09-1.19 (m, 2H), 1.26 (dd, J=8.09,2.29

Hz, 1H), 1.29-1.44 (m, 4H), 1.44-1.51 (m, 4H), 1.51-1.62 (m, 3H),1.67-1.80 (m, 7H), 1.87-1.97 (m, 1H), 2.12 (dd, J=17.09, 6.41 Hz, 1H),2.43 (dd, J=12.36, 8.09 Hz, 1H), 2.53-2.63 (m, 2H), 3.13-3.27 (m, 4H),3.55-3.68 (m, 4H), 4.75 (d, J=1.53 Hz, 1H), 4.95 (s, 1H), 5.29 (dd,J=6.10, 1.53 Hz, 1H), 7.20 (d, J=8.54 Hz, 2H), 7.92 (d, J=8.24 Hz, 2H).

Example 46 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(3-(dimethylamino)propyl)-3-methylureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using N1,N1,N3-trimethylpropane-1,3-diamine as the reactantamine. The product was isolated after reverse phase preparative HPLCpurification as a white solid (21 mg, 31% yield) mono-TFA salt. LCMS:m/z 672 (M+H⁺), retention time 1.86 min (method 2). ¹H NMR (500 MHz, 1:1mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.94 (s, 3H) 0.94 (s, 3H)1.01 (s, 3H) 1.05 (s, 3H) 1.07-1.20 (m, 5H) 1.24-1.29 (m, 2H) 1.33-1.39(m, 2H) 1.40-1.59 (m, 9H) 1.62-1.80 (m, 7H) 1.88-2.02 (m, 3H) 2.13 (dd,J=17.09, 6.41 Hz, 1H) 2.43 (dd, J=12.51, 8.24 Hz, 1H) 2.46-2.55 (m, 2H)2.87 (s, 6H) 2.98-3.10 (m, 5H) 3.34-3.49 (m, 2H) 4.76 (d, J=1.22 Hz, 1H)5.29 (dd, J=6.10, 1.83 Hz, 1H) 7.20 (m, J=8.24 Hz, 2H) 7.92 (m, J=8.24Hz, 2H).

Example 47 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(2-(methylsulfonamido)ethyl)ureido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using N-(2-aminoethyl)methanesulfonamide hydrochloride as thereactant amine. The product was isolated after reverse phase preparativeHPLC purification as a white solid (28 mg, 51% yield). LCMS: m/z 694(M+H⁺), retention time 2.17 min (method 2). ¹H NMR (400 MHz, 1:1 mixtureof CDCl3 and MeOD, MeOD lock) δ ppm 0.93 (br. s., 3H) 0.94 (s, 3H) 1.00(s, 6H) 1.04-1.16 (m, 5H) 1.23-1.43 (m, 6H) 1.45-1.56 (m, 5H) 1.59-1.83(m, 8H) 1.87-2.00 (m, 1H) 2.11 (dd, J=17.19, 6.40 Hz, 1H) 2.36 (dd,J=12.05, 8.28 Hz, 1H) 2.49-2.63 (m, 2H) 2.95 (s, 3H) 3.09-3.17 (m, 2H)3.20-3.30 (m, 2H) 4.61 (s, 1H) 4.72 (d, J=1.76 Hz, 1H) 5.29 (dd, J=6.02,1.51 Hz, 1H) 7.20 (m, J=8.28 Hz, 2H) 7.92 (m, J=8.28 Hz, 2H).

Example 48 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(1H-indol-1-yl)ethyl)-3-methylureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 2-(1H-indol-1-yl)-N-methylethanamine as the reactantamine. The product was isolated after reverse phase preparative HPLCpurification as a white solid (30 mg, 39% yield) mono-TFA salt. LCMS:m/z 730 (M+H⁺), retention time 2.73 min (method 2). ¹H NMR (500 MHz, 1:1mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.94 (br. s., 3H) 0.94 (br.s., 3H) 0.95 (br. s., 3H) 0.97 (s, 3H) 0.99 (s, 3H) 1.01-1.12 (m, 2H)1.21-1.29 (m, 3H) 1.32-1.37 (m, 2H) 1.38-1.53 (m, 7H) 1.54-1.73 (m, 7H)1.79-1.92 (m, 1H) 2.09 (dd, J=17.09, 6.41 Hz, 1H) 2.19 (td, J=10.61,4.43 Hz, 1H) 2.42 (s, 3H) 2.48-2.57 (m, 2H) 3.60 (ddd, J=14.50, 5.49,5.34 Hz, 1H) 3.71 (ddd, J=14.65, 5.65, 5.34 Hz, 1H) 4.28-4.39 (m, 2H)4.60 (br. s., 1H) 4.69 (s, 1H) 5.27 (d, J=6.10 Hz, 1H) 6.51 (d, J=3.05Hz, 1H) 7.05-7.12 (m, 2H) 7.15-7.22 (m, 3H) 7.38 (d, J=8.24 Hz, 1H) 7.61(d, J=7.93 Hz, 1H) 7.92 (d, J=8.24 Hz, 2H).

Example 49 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(3-(N-methylmethylsulfonamido)propyl)ureido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using N-(3-aminopropyl)-N-methylmethanesulfonamide as thereactant amine. The product was isolated after reverse phase preparativeHPLC purification as a white solid (36 mg, 62% yield). LCMS: m/z 730(M+H⁺), retention time 2.25 min (method 2). ¹H NMR (500 MHz, 1:1 mixtureof CDCl3 and MeOD, MeOD lock) δ ppm 0.93 (s, 3H) 0.94 (s, 3H) 1.00 (s,6H) 1.05-1.15 (m, 5H) 1.21-1.41 (m, 5H) 1.41-1.59 (m, 6H) 1.62-1.81 (m,10H) 1.88-1.99 (m, 1H) 2.11 (dd, J=17.09, 6.41 Hz, 1H) 2.35 (dd,J=12.36, 8.09 Hz, 1H) 2.50-2.63 (m, 2H) 2.85 (s, 3H) 2.86 (s, 3H)3.12-3.23 (m, 4H) 4.61 (s, 1H) 4.72 (d, J=1.53 Hz, 1H) 5.25-5.32 (m, 1H)7.20 (m, J=8.24 Hz, 2H) 7.92 (m, J=8.24 Hz, 2H).

Example 50 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(2-(N-methylmethylsulfonamido)ethyl)ureido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using N-(2-aminoethyl)-N-methylmethanesulfonamide as thereactant amine. The product was isolated after reverse phase preparativeHPLC purification as a white solid (37 mg, 65% yield). LCMS: m/z 708(M+H⁺), retention time 2.25 min (method 2). ¹H NMR (500 MHz, 1:1 mixtureof CDCl3 and MeOD, MeOD lock) δ ppm 0.93 (br. s., 3H) 0.94 (s, 3H) 1.00(s, 6H) 1.04-1.15 (m, 5H) 1.21-1.41 (m, 5H) 1.41-1.58 (m, 6H) 1.59-1.75(m, 7H) 1.75-1.83 (m, 1H) 1.88-2.00 (m, 1H) 2.11 (dd, J=17.09, 6.41 Hz,1H) 2.36 (dd, J=12.36, 8.09 Hz, 1H) 2.51-2.64 (m, 2H) 2.86 (s, 3H) 2.91(s, 3H) 3.18-3.25 (m, 2H) 3.31 (t, J=5.49 Hz, 2H) 4.61 (s, 1H) 4.72 (d,J=1.53 Hz, 1H) 5.28 (dd, J=6.26, 1.68 Hz, 1H) 7.20 (d, J=8.54 Hz, 2H)7.92 (d, J=8.24 Hz, 2H).

Example 51 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-(2-hydroxyethyl)-1,4-diazepane-1-carboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 2-(1,4-diazepan-1-yl)ethanol as the reactant amine. Theproduct was isolated after reverse phase preparative HPLC purificationas a white solid (49 mg, 72% yield) mono-TFA salt. LCMS: m/z 700 (M+H⁺),retention time 1.77 min (method 2). ¹H NMR (400 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm 0.94 (s, 3H) 0.94 (s, 3H) 1.00 (s, 3H)1.04 (s, 3H) 1.09 (s, 3H) 1.10-1.18 (m, 2H) 1.18-1.64 (m, 13H) 1.64-1.82(m, 7H) 1.85-2.01 (m, 1H) 2.12 (dd, J=17.19, 6.40 Hz, 1H) 2.29-2.41 (m,2H) 2.41-2.53 (m, 2H) 2.58 (d, J=13.30 Hz, 1H) 3.25-3.32 (m, 2H)3.35-3.63 (m, 6H) 3.69-4.00 (m, 4H) 4.64 (br. s., 1H) 4.75 (s, 1H) 5.29(d, J=4.77 Hz, 1H) 7.19 (m, 2H) 7.91 (m, 2H).

Example 52 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)-3-(2-hydroxyethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 2-(2-(dimethylamino)ethylamino)ethanol as the reactantamine. The product was isolated after reverse phase preparative HPLCpurification as a white solid (35 mg, 51% yield) mono-TFA salt. LCMS:m/z 688 (M+H⁺), retention time 1.79 min (method 2). ¹H NMR (500 MHz, 1:1mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.93 (br. s., 3H) 0.94 (br.s., 3H) 1.01 (br. s., 3H) 1.02 (br. s., 3H) 1.06-1.18 (m, 5H) 1.20-1.66(m, 12H) 1.66-1.81 (m, 7H) 1.81-2.01 (m, 2H) 2.12 (dd, J=17.09, 6.41 Hz,1H) 2.37 (dd, J=12.05, 8.09 Hz, 1H) 2.46-2.61 (m, 2H) 2.93 (s, 6H)3.21-3.31 (m, 2H) 3.48-3.61 (m, 3H) 3.72-3.79 (m, 2H) 4.61 (br. s., 1H)4.74 (br. s., 1H) 5.23-5.35 (m, 1H) 7.20 (d, J=8.24 Hz, 2H) 7.92 (d,J=8.24 Hz, 2H).

Example 53 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(carboxymethyl)-3-(2-morpholinoethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using ethyl 2-(2-morpholinoethylamino)acetate as the reactantamine. The product was isolated after reverse phase preparative HPLCpurification as a white solid (5 mg, 6% yield) mono-TFA salt. LCMS: m/z744 (M+H⁺), retention time 1.81 min (method 2). ¹H NMR (500 MHz, 1:1mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.94 (br. s., 3H) 0.94 (s,3H) 1.01 (s, 3H) 1.02 (s, 3H) 1.10 (d, J=2.44 Hz, 1H) 1.11-1.16 (m, 4H)1.19-1.64 (m, 12H) 1.64-1.80 (m, 7H) 1.87-1.98 (m, 1H) 2.13 (dd,J=17.09, 6.41 Hz, 1H) 2.35 (dd, J=12.51, 8.24 Hz, 1H) 2.47-2.59 (m, 2H)3.23-3.30 (m, 2H) 3.37 (s, 3H) 3.58 (td, J=10.38, 4.88 Hz, 1H) 3.70-4.03(m, 6H) 4.72 (s, 1H) 4.78 (d, J=1.53 Hz, 1H) 5.29 (dd, J=6.10, 1.53 Hz,1H) 7.20 (m, J=8.24 Hz, 2H) 7.92 (m, J=8.24 Hz, 2H).

Example 54 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(4-methylpiperazine-1-carboxamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 1-methylpiperazine as the reactant amine. The productwas isolated after reverse phase preparative HPLC purification as awhite solid (49 mg, 75% yield) mono-TFA salt. LCMS: m/z 656 (M+H⁺),retention time 2.44 min (method 11). ¹H NMR (500 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm 0.94 (br. s., 3H) 0.94 (s, 3H) 1.00 (s,3H) 1.03 (s, 3H) 1.05-1.19 (m, 5H) 1.23-1.28 (m, 1H) 1.31-1.42 (m, 4H)1.44-1.59 (m, 7H) 1.64-1.81 (m, 7H) 1.86-1.98 (m, 1H) 2.12 (dd, J=17.24,6.26 Hz, 1H) 2.42 (dd, J=12.36, 8.39 Hz, 1H) 2.51-2.65 (m, 2H) 2.90 (s,3H) 3.34 (br. s., 4H) 3.96 (br. s., 2H) 4.64 (br. s., 1H) 4.75 (d,J=1.22 Hz, 1H) 5.29 (dd, J=6.26, 1.68 Hz, 1H) 7.20 (m, J=8.24 Hz, 2H)7.92 (m, J=8.55 Hz, 2H).

Example 55 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(1,4-diazepane-1-carboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using homopiperazine as the reactant amine. The product wasisolated after reverse phase preparative HPLC purification as a whitesolid (33 mg, 53% yield) mono-TFA salt. LCMS: m/z 656 (M+H⁺), retentiontime 2.43 min (method 11). ¹H NMR (400 MHz, 1:1 mixture of CDCl3 andMeOD, MeOD lock) δ ppm 0.94 (s, 6H) 1.00 (s, 3H) 1.04 (s, 3H) 1.09 (s,3H) 1.10-1.22 (m, 2H) 1.24-1.30 (m, 1H) 1.34-1.59 (m, 11H) 1.64-1.82 (m,7H) 1.86-2.01 (m, 1H) 2.12 (dd, J=17.07, 6.27 Hz, 1H) 2.18-2.29 (m, 2H)2.42-2.53 (m, 2H) 2.59 (d, J=13.30 Hz, 1H) 3.20-3.31 (m, 4H) 3.48-3.62(m, 2H) 3.76 (t, J=4.27 Hz, 2H) 4.47 (s, 1H) 4.64 (s, 1H) 4.75 (s, 1H)5.29 (d, J=4.77 Hz, 1H) 7.20 (m, J=8.03 Hz, 2H) 7.92 (m, J=8.03 Hz, 2H).

Example 56 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(carboxymethyl)-3-oxopiperazine-1-carboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using ethyl 2-(3-oxopiperazin-2-yl)acetate as the reactantamine. The product was isolated after reverse phase preparative HPLCpurification as a white solid (38 mg, 64% yield). LCMS: m/z 714 (M+H⁺),retention time 2.66 min (method 11). This material is a diastereomericmixture in a ratio of approximately 1:1. ¹H NMR (400 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm 0.91-0.97 (m, 6H) 0.97-1.04 (m, 6H)1.05-1.17 (m, 5H) 1.19-1.64 (m, 13H) 1.65-1.80 (m, 7H) 1.80-2.08 (m, 3H)2.12 (dt, J=17.07, 6.02 Hz, 1H) 2.23 (dd, J=12.30, 8.28 Hz, 0.5H)2.34-2.44 (m, 0.5H) 2.58 (d, J=13.30 Hz, 0.5H) 2.65-2.76 (m, 1H)2.80-2.96 (m, 2H) 2.97-3.13 (m, 2H) 3.14-3.24 (m, 1H) 3.50-3.64 (m,1.5H) 3.94-4.03 (m, 0.5H) 4.07 (dd, J=13.80, 2.76 Hz, 0.5H) 4.70-4.80(m, 2H) 5.25-5.32 (m, 1H) 7.19 (d, J=8.03 Hz, 2H) 7.92 (d, 2H)

Example 57 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-oxopiperazine-1-carboxamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using piperazin-2-one as the reactant amine. The product wasisolated after reverse phase preparative HPLC purification as a whitesolid (7 mg, 12% yield). LCMS: m/z 656 (M+H⁺), retention time 2.71 min(method 11). ¹H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock)δ ppm 0.94 (s, 3H) 0.94 (s, 3H) 1.00 (s, 3H) 1.03 (s, 3H) 1.10 (s, 3H)1.10-1.20 (m, 2H) 1.25 (d, J=10.07 Hz, 1H) 1.29-1.44 (m, 4H) 1.44-1.63(m, 7H) 1.65-1.80 (m, 7H) 1.89-2.00 (m, 1H) 2.13 (dd, J=17.09, 6.41 Hz,1H) 2.46 (dd, J=12.51, 8.24 Hz, 1H) 2.49-2.61 (m, 2H) 3.36-3.45 (m, 2H)3.54-3.67 (m, 2H) 3.91-4.02 (m, 1H) 4.02-4.13 (m, 1H) 4.64 (d, J=1.22Hz, 1H) 4.76 (d, J=1.22 Hz, 1H) 5.29 (dd, J=6.26, 1.68 Hz, 1H) 7.20 (d,J=8.24 Hz, 2H) 7.92 (d, J=8.55 Hz, 2H).

Example 58 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-aminoethyl)-3-(carboxymethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was formed as a byproduct during the ester hydrolysisstep in the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-oxopiperazine-1-carboxamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid. Purification by reverse phase preparative HPLC gave a white solid(22 mg, 33% yield) mono-TFA salt. LCMS: m/z 674 (M+H⁺), retention time2.41 min (method 11). ¹H NMR (400 MHz, 1:1 mixture of CDCl3 and MeOD,MeOD lock) δ ppm 0.94 (s, 3H) 0.94 (s, 3H) 1.01 (s, 3H) 1.02 (s, 3H)1.07-1.18 (m, 5H) 1.20-1.59 (m, 12H) 1.60-1.79 (m, 8H) 1.86-2.01 (m, 1H)2.12 (dd, J=17.07, 6.27 Hz, 1H) 2.37-2.51 (m, 2H) 2.51-2.60 (m, 1H)3.05-3.18 (m, 2H) 3.47 (ddd, J=15.37, 5.46, 5.27 Hz, 1H) 3.70-3.82 (m,1H) 3.93-4.06 (m, 2H) 4.62 (s, 1H) 4.75 (d, J=1.51 Hz, 1H) 5.29 (dd,J=6.02, 1.51 Hz, 1H) 7.20 (m, J=8.28 Hz, 2H) 7.92 (m, J=8.28 Hz, 2H).

Example 59 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-(tert-butoxycarbonyl)-2-(carboxymethyl)piperazine-1-carboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using tert-butyl3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate as the reactant amine.The product was isolated after reverse phase preparative HPLCpurification as a white solid (39 mg, 63% yield). LCMS: m/z 800 (M+H⁺),retention time 2.94 min (method 11). This material is a diastereomericmixture in a ratio of approximately 2:1. ¹H NMR (500 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm ¹H NMR (500 MHz, MeOD) δ ppm 0.89-0.97(m, 6H) 0.97-1.05 (m, 6H) 1.05-1.18 (m, 5H) 1.25 (d, J=3.36 Hz, 1H)1.29-1.44 (m, 5H) 1.48 (d, J=5.80 Hz, 13H) 1.51-1.62 (m, 3H) 1.65-1.80(m, 7H) 1.81-2.00 (m, 2H) 2.12 (ddd, J=17.09, 6.10, 3.66 Hz, 1H)2.27-2.42 (m, 1H) 2.57 (dd, J=17.24, 4.12 Hz, 1H) 2.63 (dd, J=12.82,9.77 Hz, 2H) 2.75 (br. s., 0.5H) 2.88 (d, J=7.02 Hz, 1.5H) 2.95-3.04 (m,1H) 3.09 (br. s., 0.5H) 3.80 (d, J=11.60 Hz, 0.5H) 3.91 (d, J=12.21 Hz,0.5H) 4.03 (d, J=10.38 Hz, 1H) 5.29 (dd, J=4.27, 2.14 Hz, 1H) 7.20 (dd,J=8.24, 2.44 Hz, 2H) 7.92 (d, J=7.32 Hz, 2H).

Example 60 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(5-(dimethylamino)pentyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using N1,N1-dimethylpentane-1,5-diamine as the reactantamine. The mono-TFA salt product was isolated after reverse phasepreparative HPLC purification as a white solid (21 mg, 57% yield). LCMS:m/z 686 (M+H⁺), retention time 2.44 min (method 11). ¹H NMR (500 MHz,1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.93 (br. s., 3H) 0.94(s, 3H) 1.00 (br. s., 3H) 1.01 (br. s., 3H) 1.04-1.16 (m, 5H) 1.23-1.26(m, 1H) 1.28-1.44 (m, 7H) 1.44-1.59 (m, 7H) 1.59-1.67 (m, 2H) 1.67-1.84(m, 8H) 1.86-1.98 (m, 1H) 2.12 (dd, J=17.40, 6.41 Hz, 1H) 2.34 (dd,J=12.21, 8.24 Hz, 1H) 2.50-2.63 (m, 2H) 2.86 (s, 6H) 3.03-3.17 (m, 4H)4.61 (s, 1H) 4.72 (d, J=1.53 Hz, 1H) 5.24-5.32 (m, 1H) 7.20 (m, J=8.24Hz, 2H) 7.92 (m, J=8.24 Hz, 2H).

Example 61 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-(tert-butoxycarbonyl)-2-(hydroxymethyl)piperazine-1-carboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate asthe reactant amine. The product was isolated as a mixture of twodiastereomers after reverse phase preparative HPLC purification as awhite solid (68 mg, 60% yield). LCMS: m/z 772 (M+H⁺), retention time2.91 and 2.99 min (method 11). This material is a diastereomeric mixturein a ratio of approximately 5:4. ¹H NMR (400 MHz, 1:1 mixture of CDCl3and MeOD, MeOD lock) δ ppm 0.89-0.98 (m, 6H) 0.98-1.04 (m, 6H) 1.05-1.18(m, 5H) 1.20-1.44 (m, 6H) 1.47 (d, J=2.26 Hz, 9H) 1.48-1.61 (m, 6H)1.62-1.77 (m, 7H) 1.80-2.01 (m, 2H) 2.12 (dd, J=16.81, 6.02 Hz, 1H)2.32-2.42 (m, 1H) 2.46-2.56 (m, 1H) 2.60 (dd, J=13.30, 2.51 Hz, 1H)2.98-3.15 (m, 2H) 3.21 (ddd, J=18.63, 13.87, 4.64 Hz, 1H) 3.61-3.69 (m,1H) 3.71-3.91 (m, 4H) 3.94-4.06 (m, 1H) 4.61 (d, J=8.78 Hz, 1H) 4.74(dd, J=10.79, 1.25 Hz, 1H) 5.24-5.33 (m, 1H) 7.20 (dd, J=8.41, 1.88 Hz,2H) 7.86-7.92 (m, 1H) 7.93 (s, 1H).

Example 62 Preparation of4-(tert-butoxycarbonyl)-1-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-carboxyphenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-ylcarbamoyl)piperazine-2-carboxylicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate asthe reactant amine. The product was isolated as a mixture of twodiastereomers after reverse phase preparative HPLC purification as awhite solid (76 mg, 62% yield). LCMS: m/z 786 (M+H⁺), retention time2.84 min (method 11). This material is a diastereomeric mixture in aratio of approximately 1:1. ¹H NMR (500 MHz, 1:1 mixture of CDCl3 andMeOD, MeOD lock) δ ppm 0.93 (br. s., 3H) 0.94 (br. s., 3H) 1.01 (s, 3H)1.02 (s, 3H) 1.04-1.18 (m, 5H) 1.19-1.43 (m, 6H) 1.46 (d, J=2.75 Hz, 9H)1.47-1.61 (m, 6H) 1.61-1.80 (m, 8H) 1.91-2.05 (m, 1H) 2.12 (dd, J=17.09,6.41 Hz, 1H) 2.43 (dd, J=12.21, 8.24 Hz, 1H) 2.46-2.53 (m, 1H) 2.53-2.62(m, 1H) 2.98 (br. s., 1H) 3.17 (d, J=9.77

Hz, 1H) 3.35-3.44 (m, 1H) 3.50 (d, J=9.77 Hz, 1H) 4.09 (br. s., 1H) 4.60(d, J=13.73 Hz, 1H) 4.63 (br. s., 1H) 4.68 (br. s., 1H) 4.75 (br. s.,1H) 5.29 (d, J=4.58 Hz, 1H) 7.20 (d, J=8.24 Hz, 2H) 7.92 (d, J=8.24 Hz,2H).

Example 63 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-carboxyphenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-ylcarbamoyl)piperazine-2-carboxylicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using methyl piperazine-2-carboxylate as the reactant amine.The product was isolated as a mixture of two diastereomers after reversephase preparative HPLC purification as a white solid (75 mg, 41% yield)mono-TFA salt. LCMS: m/z 686 (M+H⁺), retention time 2.46 min (method11). This material is a diastereomeric mixture in a ratio ofapproximately 1:1. ¹H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeODlock) δ ppm 0.93 (br. s., 3H) 0.93 (br. s., 3H) 0.99 (s, 3H) 1.02 (s,3H) 1.05-1.18 (m, 5H) 1.25 (d, J=7.63 Hz, 1H) 1.28-1.42 (m, 4H)1.42-1.52 (m, 5H) 1.52-1.64 (m, 2H) 1.65-1.84 (m, 7H) 1.87-1.99 (m, 1H)2.11 (dd, J=17.09, 6.41 Hz, 1H) 2.41 (td, J=11.90, 8.85 Hz, 1H) 2.55(dd, J=13.43, 2.75 Hz, 1H) 2.63 (tt, J=10.72, 5.46 Hz, 1H) 3.07-3.18 (m,0.5H) 3.19-3.27 (m, 0.5H) 3.34-3.51 (m, 2H) 3.57-3.71 (m, 1H) 3.71-3.83(m, 1H) 3.98-4.05 (m, 0.5H) 4.07-4.16 (m, 1H) 4.16-4.25 (m, 0.5H) 4.63(s, 1H) 4.76 (br. s., 1H) 5.28 (d, J=4.88 Hz, 1H) 7.19 (m, J=8.24 Hz,2H) 7.92 (m, J=8.24 Hz, 2H).

Example 64 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(6-hydroxy-1,4-diazepane-1-carboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed above for the C-17 urea formation and subsequent esterhydrolysis using 1,4-diazepan-6-ol dihydrobromide as the reactant amine.The product was isolated as a mixture of two diastereomers after reversephase preparative HPLC purification as a white solid (30 mg, 35% yield)mono-TFA salt. LCMS: m/z 672 (M+H⁺), retention time 2.42 min (method11). This material is a diastereomeric mixture in a ratio ofapproximately 1:1. ¹H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeODlock) δ ppm 0.89-0.96 (m, 6H) 0.97-1.05 (m, 6H) 1.05-1.17 (m, 5H)1.22-1.42 (m, 6H) 1.42-1.60 (m, 7H) 1.64-1.80 (m, 7H) 1.82-2.02 (m, 2H)2.12 (dd, J=17.09, 6.10 Hz, 1H) 2.49-2.65 (m, 2H) 3.12-3.32 (m, 4H)3.36-3.44 (m, 1H) 3.45-3.53 (m, 1H) 3.78 (d, J=15.56 Hz, 0.5H) 3.95 (d,J=15.56 Hz, 0.5H) 4.25-4.44 (m, 2H) 4.62 (d, J=8.85 Hz, 1H) 4.71 (br.s., 0.5H) 4.75 (br. s., 0.5H) 5.29 (d, J=6.10 Hz, 1H) 5.69 (s, 0.5H)5.74 (s, 0.5H) 7.20 (dd, J=8.24, 1.53 Hz, 2H) 7.92 (d, J=7.93 Hz, 2H).

Example 65 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)(2-hydroxyethyl)carbamoyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed for the C-17 urea formation and subsequent ester hydrolysisusing the mixture of2-((tert-butyl(dimethyl)silyl)oxy)-N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)ethanamineand 2-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)ethanol acquired inStep 3 below as the reactant amine. The urea formation step gave thedesilylated material directly as the major product of the reaction, sono desilylation step was necessary. After ester hydrolysis, the mono-TFAsalt product was isolated by reverse phase preparative HPLC purificationas a white solid (96 mg, 57% yield). LCMS: m/z 778 (M+H⁺), retentiontime 2.43 min (method 11). ¹H NMR (400 MHz, 1:1 mixture of CDCl3 andMeOD, MeOD lock) δ ppm 0.94 (br. s., 3H) 0.94 (s, 3H) 1.01 (br. s., 3H)1.02 (s, 3H) 1.06-1.16 (m, 5H) 1.20-1.45 (m, 6H) 1.45-1.64 (m, 6H)1.64-1.79 (m, 6H) 1.81-2.00 (m, 2H) 2.12 (dd, J=17.07, 6.27 Hz, 1H) 2.38(dd, J=11.80, 8.03 Hz, 1H) 2.48-2.63 (m, 2H) 3.16 (br. s., 2H) 3.30 (br.s., 1H) 3.37 (br. s., 4H) 3.43-3.58 (m, 3H) 3.60 (br. s., 4H) 3.76 (br.s., 2H) 4.61 (d, J=1.51 Hz, 1H) 4.73 (d, J=1.25 Hz, 1H) 5.29 (d, J=4.77Hz, 1H) 7.20 (m, J=8.28 Hz, 2H) 7.92 (m, J=8.28 Hz, 2H).

Synthesis of amine used in preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)(2-hydroxyethyl)carbamoyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation ofN-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide

A mixture of 4-(2-aminoethyl)thiomorpholine 1,1-dioxide (2.00 g, 11.2mmol) and triethylamine (1.42 g, 14.0 mmol) in DCM (100 mL) was cooledin an ice bath and treated slowly with 2-nitrobenzene-1-sulfonylchloride (2.49 g, 11.2 mmol). The mixture was removed from the ice bathand stirred at rt for 18 h. The resulting mixture was washed with water(2×50 mL) and the combined aqueous washes were extracted with DCM (50mL). The organic phases were combined, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to a yellow solid.Purification by silica gel chromatography (linear gradient 100% DCM to100:1 DCM:MeOH) gave the title compound as a pale yellow solid (3.47 g,85% yield). LCMS: m/z 364 (M+H⁺), retention time 0.98 min (method 11).¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.71 (t, J=5.49 Hz, 2H) 2.96 (br.s., 4H) 3.05 (br. s., 4H) 3.20 (q, J=5.49 Hz, 2H) 5.93 (br. s., 1H)7.73-7.84 (m, 2H) 7.84-7.93 (m, 1H) 8.11-8.23 (m, 1H).

Step 2. Preparation ofN-(2-((tert-butyl(dimethyl)silyl)oxy)ethyl)-N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide

N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide(0.400 g, 1.10 mmol) was combined with cesium carbonate (0.538 g, 1.65mmol) in DMF (5 mL). The slurry was stirred at rt for 30 min, then to itwas added (2-bromoethoxy)(tert-butyl)dimethylsilane (0.527 g, 2.20mmol). The resulting mixture was stirred at rt for 18 h. Dilution withethyl acetate (60 mL) and water (40 mL) followed by shaking gave aseparation of phases. The organic phase was isolated, washed with water(2×30 mL) and brine (25 mL), dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to a residue. Purification by silicagel chromatography (gradient 100% DCM to 100:1 DCM:MeOH) gave the titlecompound as a yellow solid (0.560 g, 98% yield). LCMS: m/z 522 (M+H⁺),retention time 2.22 min (method 11). ¹H NMR (500 MHz, CHLOROFORM-d) δppm 0.01 (s, 6H) 0.86 (s, 9H) 2.75 (t, J=5.95 Hz, 2H) 3.05 (s, 8H) 3.44(t, J=5.49 Hz, 2H) 3.57 (t, J=6.41 Hz, 2H) 3.70 (t, J=5.49 Hz, 2H)7.63-7.78 (m, 3H) 8.02-8.11 (m, 1H).

Step 3. Preparation of a mixture of2-((tert-butyl(dimethyl)silyl)oxy)-N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)ethanamineand 2-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)ethanol

N-(2-((tert-butyl(dimethyl)silyl)oxy)ethyl)-N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide(0.550 g, 1.05 mmol) and thiophenol (0.348 g, 3.16 mmol) were combinedin dry acetonitrile (10 mL). Potassium carbonate (0.583 g, 4.22 mmol)was added and the mixture was stirred at rt for 18 h. The mixture wasdiluted with ethyl acetate and filtered to remove unwanted solids. Thecrude filtrate was concentrated in vacuo, redissolved in methanol, andloaded onto a strong cation exchange resin cartridge to capture thedesired product. Undesired materials were eluted from the cartridge withmethanol, and then the desired material was released from the resin byelution with 2M ammonia in methanol. Concentration in vacuo gave ayellow oil (0.300 g, 85% yield). ¹H NMR revealed that the materialcollected was a roughly 2:3 mixture of desired product and desilylateddesired material. No further purification was performed and the mixturewas carried forward to the next step.

Example 66 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)(3-hydroxypropyl)carbamoyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed for the C-17 urea formation and subsequent ester hydrolysisusing3-((tert-butyl(dimethyl)silyl)oxy)-N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-1-propanamineas the reactant amine (prepared as described below). The urea formationstep gave the desilylated material directly as the major product of thereaction, so no desilylation step was necessary. After ester hydrolysis,the mono-TFA salt product was isolated by reverse phase preparative HPLCpurification as a white solid (86 mg, 53% yield). LCMS: m/z 792 (M+H⁺),retention time 2.45 min (method 11). ¹H NMR (500 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm 0.93 (br. s., 3H) 0.94 (br. s., 3H)1.00 (s, 3H) 1.02 (s, 3H) 1.07-1.17 (m, 5H) 1.25 (d, J=7.02 Hz, 1H)1.28-1.45 (m, 5H) 1.45-1.65 (m, 7H) 1.65-1.75 (m, 6H) 1.75-1.85 (m, 2H)1.85-1.99 (m, 2H) 2.12 (dd, J=17.09, 6.41 Hz, 1H) 2.41 (dd, J=12.05,8.09 Hz, 1H) 2.58 (d, J=13.43 Hz, 1H) 2.66 (td, J=10.91, 4.73 Hz, 1H)3.09 (br. s., 2H) 3.39-3.52 (m, 2H) 3.54 (br. s., 4H) 3.55-3.63 (m, 2H)3.67 (ddd, J=10.76, 5.26, 5.04 Hz, 1H) 4.62 (s, 1H) 4.75 (s, 1H) 5.29(d, J=4.58 Hz, 1H) 7.20 (m, J=8.24 Hz, 2H) 7.92 (m, J=8.24 Hz, 2H).

Synthesis of amine used in preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)(3-hydroxypropyl)carbamoyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation ofN-(3-((tert-butyl(dimethyl)silyl)oxy)propyl)-N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide

N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide(0.400 g, 1.10 mmol) was combined with cesium carbonate (0.538 g, 1.65mmol) in DMF (5 mL). The slurry was stirred at rt for 30 min, then to itwas added (3-bromopropoxy)(tert-butyl)dimethylsilane (0.558 g, 2.20mmol). The resulting mixture was stirred at rt for 18 h. LCMS indicatedincomplete conversion, so additional(3-bromopropoxy)(tert-butyl)dimethylsilane (0.558 g, 2.20 mmol) andcesium carbonate (0.538 g, 1.65 mmol) were added and the mixture washeated to 70° C. for 1 h. Dilution with ethyl acetate (60 mL) and water(40 mL) followed by shaking gave a separation of phases. The organicphase was isolated, washed with water (2×30 mL) and brine (25 mL), driedover anhydrous magnesium sulfate, filtered and concentrated in vacuo toa residue. Purification by silica gel chromatography (gradient 100% DCMto 100:1 DCM:MeOH) gave the title compound as a sticky yellow material,partially crystalline (0.548 g, 93% yield). LCMS: m/z 536 (M+H⁺),retention time 2.26 min (method 11). ¹H NMR (400 MHz, CHLOROFORM-d) δppm 0.02 (s, 6H) 0.87 (s, 9H) 1.63-1.75 (m, 2H) 2.72 (t, J=6.40 Hz, 2H)3.07 (s, 8H) 3.32-3.40 (m, 2H) 3.47 (t, J=6.40 Hz, 2H) 3.56 (t, J=5.90Hz, 2H) 7.63-7.76 (m, 3H) 8.08 (dd, J=7.53, 1.76 Hz, 1H).

Step 2. Preparation of3-((tert-butyl(dimethyl)silyl)oxy)-N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-1-propanamine

N-(3-((tert-butyl(dimethyl)silyl)oxy)propyl)-N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide(0.540 g, 1.01 mmol) and thiophenol (0.333 g, 3.02 mmol) were combinedin dry acetonitrile (10 mL). Potassium carbonate (0.557 g, 4.03 mmol)was added and the mixture was stirred at rt for 18 h. The mixture wasdiluted with ethyl acetate and filtered to remove unwanted solids. Thecrude filtrate was concentrated in vacuo, redissolved in methanol, andloaded onto a strong cation exchange resin cartridge to capture thedesired product. Undesired materials were eluted from the cartridge withmethanol, and then the desired material was released from the resin byelution with 2M ammonia in methanol. Concentration in vacuo gave thetitle compound as a yellow oil (0.294 g, 83% yield). No furtherpurification was performed and the mixture was carried forward to thenext step. LCMS: m/z 351 (M+H⁺), ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm0.06 (s, 6H) 0.90 (s, 9H) 1.75 (quin, J=6.46 Hz, 2H) 2.69-2.72 (m, 2H)2.72-2.80 (m, 4H) 3.00-3.11 (m, 8H) 3.70 (t, J=6.02 Hz, 2H).

Example 67 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)(2-methoxyethyl)carbamoyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed for the C-17 urea formation and subsequent ester hydrolysisusing 2-(1,1-dioxido-4-thiomorpholinyl)-N-(2-methoxyethyl)ethanamine(prepared as described below) as the reactant amine. After esterhydrolysis, the mono-TFA salt product was isolated by reverse phasepreparative HPLC purification as a white solid (89 mg, 57% yield). LCMS:m/z 792 (M+H⁺), retention time 2.48 min (method 11). ¹H NMR (500 MHz,1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.94 (br. s., 3H) 0.95(s, 3H) 1.01 (s, 3H) 1.02 (s, 3H) 1.06-1.17 (m, 5H) 1.24-1.29 (m, 1H)1.30-1.42 (m, 4H) 1.44-1.55 (m, 6H) 1.55-1.65 (m, 2H) 1.65-1.77 (m, 6H)1.82 (td, J=12.13, 3.20 Hz, 1H) 1.86-1.98 (m, 1H) 2.13 (dd, J=17.09,6.41 Hz, 1H) 2.38 (dd, J=12.36, 8.09 Hz, 1H) 2.47 (td, J=10.99, 5.19 Hz,1H) 2.51-2.61 (m, 1H) 3.03-3.19 (m, 2H) 3.34-3.44 (m, 5H) 3.51 (s, 3H)3.52-3.69 (m, 8H) 4.64 (s, 1H) 4.73 (s, 1H) 5.29 (d, J=4.58 Hz, 1H) 7.20(m, J=8.24 Hz, 2H) 7.92 (m, J=8.24 Hz, 2H).

Synthesis of amine used in preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)(2-methoxyethyl)carbamoyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation ofN-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-N-(2-methoxyethyl)-2-nitrobenzenesulfonamide

N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide(0.400 g, 1.10 mmol) was combined with cesium carbonate (0.538 g, 1.65mmol) in DMF (5 mL). The slurry was stirred at rt for 30 min, then to itwas added 1-bromo-2-methoxyethane (0.306 g, 2.20 mmol). The resultingmixture was stirred at rt for 72 h. LCMS indicated incompleteconversion, so additional 1-bromo-2-methoxyethane (0.306 g, 2.20 mmol)and cesium carbonate (0.538 g, 1.65 mmol) were added and the mixture washeated to 70° C. for 1 h. Dilution with ethyl acetate (60 mL) and water(40 mL) followed by shaking gave a separation of phases. The organicphase was isolated, washed with water (2×30 mL) and brine (25 mL), driedover anhydrous magnesium sulfate, filtered and concentrated in vacuo toa residue. Purification by silica gel chromatography (gradient 100% DCMto 60:1 DCM:MeOH) gave the title compound as a yellow oil (0.486 g, 105%yield). LCMS: m/z 422 (M+H⁺), retention time 1.35 min (method 11). ¹HNMR (500 MHz, CHLOROFORM-d) δ ppm 2.72 (t, J=6.41 Hz, 2H) 3.01 (s, 8H)3.21 (s, 3H) 3.39-3.52 (m, 6H) 7.62-7.66 (m, 1H) 7.66-7.74 (m, J=7.48,7.32, 7.32, 7.32, 1.68 Hz, 2H) 8.01 (dd, J=7.78, 1.68 Hz, 1H).

Step 2. Preparation of2-(1,1-dioxido-4-thiomorpholinyl)-N-(2-methoxyethyl)ethanamine

N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-N-(2-methoxyethyl)-2-nitrobenzenesulfonamide(0.470 g, 1.12 mmol) and thiophenol (0.369 g, 3.35 mmol) were combinedin dry acetonitrile (10 mL). Potassium carbonate (0.616 g, 4.46 mmol)was added and the mixture was stirred at rt for 18 h. The mixture wasdiluted with ethyl acetate and filtered to remove unwanted solids. Thecrude filtrate was concentrated in vacuo, redissolved in methanol, andloaded onto a strong cation exchange resin cartridge to capture thedesired product. Undesired materials were eluted from the cartridge withmethanol, and then the desired material was released from the resin byelution with 2M ammonia in methanol. Concentration in vacuo gave thetitle compound as a yellow solid (0.222 g, 84% yield). No furtherpurification was performed and the mixture was carried forward to thenext step. LCMS: m/z 237 (M+H⁺), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm2.15 (br. s., 1H) 2.66-2.71 (m, 2H) 2.71-2.77 (m, 2H) 2.82 (t, J=5.04Hz, 2H) 2.97-3.05 (m, 4H) 3.05-3.10 (m, 4H) 3.37 (s, 3H) 3.51 (t, J=5.04Hz, 2H).

Example 68 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)(3-methoxypropyl)carbamoyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed for the C-17 urea formation and subsequent ester hydrolysisusing N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-3-methoxy-1-propanamine(prepared as described below) as the reactant amine. After esterhydrolysis, the mono-TFA salt product was isolated by reverse phasepreparative HPLC purification as a white solid (132 mg, 82% yield).LCMS: m/z 806 (M+H⁺), retention time 2.52 min (method 11). ¹H NMR (400MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.94 (br. s., 3H)0.95 (s, 3H) 1.01 (s, 3H) 1.03 (s, 3H) 1.10 (s, 3H) 1.11-1.21 (m, 2H)1.21-1.42 (m, 5H) 1.43-1.65 (m, 8H) 1.65-1.77 (m, 6H) 1.77-1.98 (m, 5H)2.12 (dd, J=17.07, 6.27 Hz, 1H) 2.40 (dd, J=12.17, 8.16 Hz, 1H)2.55-2.67 (m, 2H) 3.01 (t, J=6.15 Hz, 2H) 3.29 (d, J=5.02 Hz, 4H)3.34-3.42 (m, 1H) 3.42-3.59 (m, 11H) 4.74 (d, J=1.51 Hz, 1H) 5.24-5.34(m, 1H) 7.20 (m, J=8.28 Hz, 2H) 7.92 (m, J=8.28 Hz, 2H).

Synthesis of amine used in preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)(3-methoxypropyl)carbamoyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation ofN-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-N-(3-methoxypropyl)-2-nitrobenzenesulfonamide

N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide(0.400 g, 1.10 mmol) was combined with cesium carbonate (0.538 g, 1.65mmol) in DMF (5 mL). The slurry was stirred at rt for 30 min, then to itwas added 1-bromo-3-methoxypropane (0.337 g, 2.20 mmol). The resultingmixture was stirred at rt for 72 h. LCMS indicated incompleteconversion, so additional 1-bromo-3-methoxypropane (0.337 g, 2.20 mmol)and cesium carbonate (0.538 g, 1.65 mmol) were added and the mixture washeated to 70° C. for 1 hour. Dilution with ethyl acetate (60 mL) andwater (40 mL) followed by shaking gave a separation of phases. Theorganic phase was isolated, washed with water (2×30 mL) and brine (25mL), dried over anhydrous magnesium sulfate, filtered and concentratedin vacuo to a residue. Purification by silica gel chromatography(gradient 100% DCM to 60:1 DCM:MeOH) gave the title compound as a yellowoil (0.522 g, 109% yield). LCMS: m/z 436 (M+H⁺), retention time 1.50 min(method 11). ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.68-1.77 (m, 2H) 2.67(t, J=6.26 Hz, 2H) 3.02 (br. s., 8H) 3.16 (s, 3H) 3.27 (t, J=5.80 Hz,2H) 3.31-3.37 (m, 2H) 3.41 (t, J=6.26 Hz, 2H) 7.61-7.65 (m, 1H)7.66-7.74 (m, 2H) 7.99-8.03 (m, 1H).

Step 2. Preparation ofN-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-3-methoxy-1-propanamine

N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-N-(3-methoxypropyl)-2-nitrobenzenesulfonamide(0.510 g, 1.17 mmol) and thiophenol (0.387 g, 3.51 mmol) were combinedin dry acetonitrile (10 mL). Potassium carbonate (0.647 g, 4.68 mmol)was added and the mixture was stirred at rt for 18 h. The mixture wasdiluted with ethyl acetate and filtered to remove unwanted solids. Thecrude filtrate was concentrated in vacuo, redissolved in methanol, andloaded onto a strong cation exchange resin cartridge to capture thedesired product. Undesired materials were eluted from the cartridge withmethanol, and then the desired material was released from the resin byelution with 2M ammonia in methanol. Concentration in vacuo gave ayellow oil (0.255 g, 87% yield). No further purification was performedand the mixture was carried forward to the next step. LCMS: m/z 251(M+H⁺), ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.77 (quin, J=6.53 Hz, 2H)2.13 (br. s., 2H) 2.62-2.68 (m, 2H) 2.68-2.75 (m, 4H) 2.93-3.11 (m, 8H)3.32 (s, 3H) 3.44 (t, J=6.15 Hz, 2H).

Example 69 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((bis(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)carbamoyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the general proceduresdescribed for the C-17 urea formation and subsequent ester hydrolysisusing2-(1,1-dioxido-4-thiomorpholinyl)-N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)ethanamine(prepared as described below) as the reactant amine. After esterhydrolysis, the bis-TFA salt product was isolated by reverse phasepreparative HPLC purification as a slightly yellow solid (109 mg, 64%yield). LCMS: m/z 895 (M+H⁺), retention time 2.42 min (method 11). ¹HNMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.94 (br.s., 3H) 0.95 (br. s., 3H) 1.01 (s, 3H) 1.04 (s, 3H) 1.12 (s, 3H)1.13-1.22 (m, 2H) 1.23-1.32 (m, 2H) 1.33-1.43 (m, 2H) 1.43-1.63 (m, 8H)1.64-1.81 (m, 7H) 1.84-1.96 (m, 1H) 2.13 (dd, J=17.24, 6.26 Hz, 1H) 2.38(td, J=10.61, 5.04 Hz, 1H) 2.47 (dd, J=12.51, 8.24 Hz, 1H) 2.50-2.59 (m,1H) 3.01 (br. s., 4H) 3.26 (br. s., 8H) 3.35-3.50 (m, 10H) 3.50-3.62 (m,2H) 4.67 (s, 1H) 4.80 (s, 1H) 5.29 (dd, J=6.10, 1.53 Hz, 1H) 7.20 (d,J=8.24 Hz, 2H) 7.92 (d, J=8.55 Hz, 2H).

Synthesis of amine used in preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((bis(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)carbamoyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation ofN,N-bis(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide

N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide(0.500 g, 1.38 mmol) was combined with 4-(2-hydroxyethyl)thiomorpholine1,1-dioxide (0.296 g, 1.65 mmol) in THF (10 mL). To this mixture wasadded triphenylphosphine (0.541 g, 2.06 mmol) and diethylazodicarboxylate (0.359 g, 2.06 mmol). The resulting mixture was stirredat rt for 72 h. The mixture was concentrated in vacuo, then redissolvedin acetonitrile. Purification by reverse phase preparative HPLC gave thetitle compound as a pale yellow solid (0.863 g, 83% yield) bis-TFA salt.LCMS: m/z 525 (M+H⁺), retention time 1.25 min (method 11). ¹H NMR (500MHz, MeOD) δ ppm 2.85 (t, J=6.71 Hz, 4H) 3.14 (d, J=5.49 Hz, 8H) 3.18(d, J=5.80 Hz, 8H) 3.51 (t, J=6.71 Hz, 4H) 7.71-7.75 (m, 1H) 7.75-7.84(m, 2H) 8.05 (d, J=7.63 Hz, 1H).

Step 2. Preparation of2-(1,1-dioxido-4-thiomorpholinyl)-N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)ethanamine

N,N-bis(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide(0.85 g, 1.13 mmol) and thiophenol (0.373 g, 3.39 mmol) were combined indry acetonitrile (10 mL). Potassium carbonate (0.936 g, 6.78 mmol) wasadded and the mixture was stirred at rt for 18 h. The mixture wasdiluted with ethyl acetate and filtered to remove unwanted solids. Thecrude filtrate was concentrated in vacuo, redissolved in methanol, andloaded onto a strong cation exchange resin cartridge to capture thedesired product. Undesired materials were eluted from the cartridge withmethanol, and then the desired material was released from the resin byelution with 2M ammonia in methanol. Concentration in vacuo gave asticky yellow oil (0.381 g, 100% yield). No further purification wasperformed and the mixture was carried forward to the next step.

Example 69-1 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-ureido-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid and4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(1-carbamoylureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(50 mg, 0.092 mmol) in DCM (1 mL) was added diisopropylethylamine (0.016mL, 0.092 mmol) and isocyanatotrimethylsilane (15.89 mg, 0.138 mmol).Theresulting mixture was stirred at rt for 48 hours. LC-MS showed desiredproduct at M+1=587.48 (2.87 min, method 13) and a side productM+1=630.48 (2.97 min, method 13). The volatiles were removed in vacuo.The crude products were obtained as yellow oil and were used in nextstep as is.

Step 2.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-ureido-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid was prepared following the method described above for the synthesisof4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, step 2. The product was isolated as white solid (15 mg, 28%).Example 69-1: LCMS: m/e 573.45 (M+H)⁺, 2.67 min (method 13). ¹H NMR (400MHz, METHANOL-d₄) δ 7.94 (d, J=8.5 Hz, 2H), 7.24 (d, J=8.5 Hz, 2H), 5.32(dd, J=6.1, 1.6 Hz, 1H), 4.78 (d, J=1.8 Hz, 1H), 4.67-4.63 (m, 1H),2.69-2.59 (m, 2H), 2.40 (dd, J=12.2, 8.2 Hz, 1H), 2.17 (dd, J=17.2, 6.4Hz, 1H), 2.04-1.84 (m, 2H), 1.74 (s, 3H), 1.82-1.67 (m, 3H), 1.63-1.48(m, 6H), 1.46-1.26 (m, 6H), 1.16 (s, 3H), 1.22-1.08 (m, 2H), 1.06 (s,3H), 1.06 (s, 3H), 0.99 (s, 3H), 0.97 (s, 3H).

Section 2. Carbamates Example 70 Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[[3-(1,1-dioxido-4-thiomorpholinyl)propoxy]carbonyl]amino]2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]

To a cloudy solution of 4-(3-hydroxypropyl)thiomorpholine 1,1-dioxide(407 mg, 2.106 mmol) in tetrahydrofuran (5 mL) was added sodium hydride(84 mg, 2.106 mmol). The resulting white slurry was stirred at rt. After40 min, the resulting paste was diluted with tetrahydrofuran (5 mL) andwas treated with methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(200 mg, 0.351 mmol) in one portion. The resulting white slurry wasstirred at rt overnight. After 16 h, the reaction was poured into 0.1NHCl (20 mL) and extracted with 2×50 mL EtOAc. The combined organic layerwas washed with brine, dried over MgSO₄, filtered and concentrated togive a white foam product. The crude material was dissolved in 2 mL THF,filtered and purified by reverse phase preparative HPLC using HPLCmethod 1 to give the mono-TFA salt of the title compound (123.1 mg,0.143 mmol, 40.6% yield) as white solid. LCMS: m/e 749.5 (M+H)⁺, 2.10min (method 6). ¹H NMR (500 MHz, 1:1 MeOD:CDCl₃) δ=7.92 (d, J=8.5 Hz,2H), 7.20 (d, J=8.5 Hz, 2H), 5.29 (dd, J=1.8, 6.1 Hz, 1H), 4.75 (d,J=1.5 Hz, 1H), 4.63 (d, J=1.2 Hz, 1H), 4.09 (t, J=5.8 Hz, 2H), 3.42 (br.s., 3H), 2.98 (t, J=7.0 Hz, 2H), 2.57 (dt, J=5.3, 10.9 Hz, 1H), 2.51 (d,J=12.8 Hz, 1H), 2.35-2.28 (m, 1H), 2.12 (dd, J=6.4, 17.1 Hz, 1H),2.02-1.88 (m, 3H), 1.82-1.65 (m, 7H), 1.65-1.45 (m, 6H), 1.45-1.19 (m,6H), 1.15-1.10 (m, 2H), 1.09 (s, 3H), 1.02 (s, 3H), 1.01 (s, 3H), 0.95(s, 3H), 0.94 (s, 3H). ¹³C NMR (1:1 MeOD:CDCl₃) δ ppm 15.2, 16.5, 17.2,19.9, 20.7, 21.8, 22.3, 26.2, 26.5, 28.2, 29.9, 30.2, 30.5, 34.5, 37.2,38.4, 38.6, 41.6, 42.7, 43.0, 48.2, 50.1, 50.5, 50.6, 51.9, 53.9, 54.6,62.4, 64.9, 78.8, 111.0, 124.9, 129.3, 129.7, 131.0, 147.4, 149.8,150.4, 156.3, 170.1.

Example 71 Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[[2-(1,1-dioxido-4-thiomorpholinyl)ethoxy]carbonyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]

The title compound was prepared in 24% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of benzoicacid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[[3-(1,1-dioxido-4-thiomorpholinyl)propoxy]carbonyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl],except 4-(2-hydroxyethyl)thiomorpholine 1,1-dioxide was used instead of4-(3-hydroxypropyl)thiomorpholine 1,1-dioxide. LCMS: m/e 735.3 (M+H)⁺,2.63 min (method 6). ¹H NMR (500 MHz, METHANOL-d₄) δ=7.95 (d, J=8.5 Hz,2H), 7.25 (d, J=8.5 Hz, 2H), 5.33 (dd, J=1.7, 6.3 Hz, 1H), 4.79 (d,J=1.8 Hz, 1H), 4.66 (s, 1H), 4.38-4.28 (m, 1H), 4.27-4.19 (m, 1H),3.56-3.43 (m, 3H), 3.31 (br. s., 2H), 3.17 (br. s., 2H), 2.71 (dt,J=5.3, 11.1 Hz, 1H), 2.57 (d, J=13.4 Hz, 1H), 2.33 (dd, J=8.4, 12.1 Hz,1H), 2.18 (dd, J=6.4, 17.1 Hz, 1H), 2.00-1.89 (m, 2H), 1.84-1.76 (m,2H), 1.75 (s, 3H), 1.73 (d, J=4.3 Hz, 1H), 1.71-1.64 (m, 1H), 1.62-1.56(m, 2H), 1.56-1.48 (m, 4H), 1.47-1.35 (m, 4H), 1.31 (dt, J=4.0, 9.3 Hz,2H), 1.15 (s, 3H), 1.12 (d, J=3.1 Hz, 1H), 1.07 (s, 6H), 0.99 (s, 3H),0.97 (s, 3H).

Example 72 Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[[4-(1,1-dioxido-4-thiomorpholinyl)butoxy]carbonyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]

The title compound was prepared in 55% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of benzoicacid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[[3-(1,1-dioxido-4-thiomorpholinyl)propoxy]carbonyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl],except 4-(4-hydroxybutyl)thiomorpholine 1,1-dioxide was used instead of4-(3-hydroxypropyl)thiomorpholine 1,1-dioxide. LCMS: m/e 763.5 (M+H)⁺,2.14 min (method 6). ¹H NMR (500 MHz, METHANOL-d₄) δ=7.95 (d, J=8.2 Hz,2H), 7.24 (d, J=8.2 Hz, 2H), 5.32 (dd, J=1.5, 6.1 Hz, 1H), 4.78 (d,J=1.5 Hz, 1H), 4.65 (s, 1H), 4.14-4.04 (m, 2H), 3.87-3.79 (m, 4H),3.62-3.51 (m, 4H), 2.69 (dt, J=5.0, 11.1 Hz, 1H), 2.56 (d, J=13.4 Hz,1H), 2.32 (dd, J=8.9, 11.3 Hz, 1H), 2.18 (dd, J=6.3, 17.2 Hz, 1H),2.00-1.91 (m, 2H), 1.91-1.82 (m, 2H), 1.82-1.75 (m, 3H), 1.74 (s, 4H),1.70-1.56 (m, 3H), 1.51 (d, J=11.0 Hz, 4H), 1.46-1.34 (m, 4H), 1.33-1.26(m, 2H), 1.14 (s, 3H), 1.13-1.09 (m, 2H), 1.08-1.06 (m, 3H), 1.06 (s,3H), 0.99 (s, 3H), 0.97 (s, 3H).

Section 3. Amides Example 73 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a cloudy solution mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.240 g, 0.441 mmol) in THF (5 mL) was added N,N-diisopropylethylamine(0.461 mL, 2.65 mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (0.369 g, 0.971 mmol) and3-(dimethylamino)propionic acid hydrochloride (0.136 g, 0.883 mmol). Thereaction mixture was stirred at rt. After 16 h, the reaction mixture wasdiluted with EtOAc (50 mL), washed with 1N HCl (5 mL), 5% NaHCO₃, brine,dried over MgSO₄, filtered and concentrated to a viscous oil product.The crude material was dissolved in THF (1 mL) and MeOH (1.5 mL),filtered and purified by reverse phase preparative HPLC using HPLCmethod 4 to give methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,TFA (93.8 mg, 0.116 mmol, 26.4% yield) as a white solid. LCMS: m/e 643.3(M+H)⁺, 4.17 min (method 8). ¹H NMR (500 MHz, 1:1 MeOD:CDCl₃)δ=7.97-7.85 (m, 2H), 7.29-7.23 (m, 2H), 7.21 (br. s., 1H), 5.32 (d,J=4.0 Hz, 1H), 4.80 (br. s., 1H), 4.67 (br. s., 1H), 3.97-3.88 (m, 3H),3.43-3.37 (m, 2H), 2.92 (br. s., 6H), 2.84-2.77 (m, 2H), 2.77-2.68 (m,2H), 2.46-2.38 (m, 1H), 2.22-2.13 (m, 1H), 2.05-1.88 (m, 2H), 1.83 (d,J=13.4 Hz, 1H), 1.75 (br. s., 5H), 1.66-1.49 (m, 7H), 1.48-1.34 (m, 4H),1.32 (br. s., 1H), 1.16 (br. s., 4H), 1.07 (br. s., 6H), 0.98 (br. s.,3H), 0.96 (br. s., 3H). ¹³C NMR (1:1 MeOD:CDCl₃) δ ppm 13.8, 15.4, 16.0,18.4, 19.9, 20.6, 21.4, 25.6, 27.5, 28.7, 29.0, 29.5, 29.7, 33.8, 34.8,36.4, 37.5, 37.5, 40.8, 41.8, 42.1, 47.0, 49.5, 49.8, 51.5, 53.3, 54.5,65.8, 102.7, 109.7, 124.3, 128.2, 128.5, 130.3, 146.7, 149.2, 150.1,167.6, 170.3.

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,TFA (87.9 mg, 0.116 mmol) in THF (5 mL) was added a solution of lithiumhydroxide monohydrate (19.49 mg, 0.464 mmol) in water (1.00 mL). Thereaction was stirred at 75° C. After 8 h, the reaction was concentratedto dryness. The crude material was dissolved in THF (1 mL) and MeOH (1.5mL), filtered and purified by reverse phase preparative HPLC using HPLCmethod 1 to give the title compound (59.5 mg, 0.078 mmol, 67.6% yield)as a white solid. LCMS: m/e 629.4 (M+H)⁺, 4.17 min (method 8). ¹H NMR(500 MHz, METHANOL-d₄) δ=7.95 (d, J=8.2 Hz, 2H), 7.24 (d, J=8.2 Hz, 3H),5.33 (dd, J=1.5, 6.1 Hz, 1H), 4.80 (d, J=1.5 Hz, 1H), 4.67 (s, 1H), 3.40(t, J=6.6 Hz, 2H), 2.92 (s, 6H), 2.88-2.69 (m, 4H), 2.42 (dd, J=8.4,12.4 Hz, 1H), 2.18 (dd, J=6.4, 17.1 Hz, 1H), 2.05-1.89 (m, 2H), 1.83 (d,J=11.3 Hz, 1H), 1.79-1.76 (m, 1H), 1.75 (s, 3H), 1.74-1.71 (m, 1H),1.66-1.56 (m, 3H), 1.56-1.49 (m, 4H), 1.47-1.28 (m, 5H), 1.22-1.17 (m,1H), 1.16 (s, 3H), 1.15-1.10 (m, 1H), 1.07 (s, 6H), 0.99 (s, 3H), 0.97(s, 3H). ¹³C NMR (MeOD) δ ppm 14.5, 16.1, 16.8, 19.1, 20.6, 21.3, 22.1,26.2, 28.2, 29.4, 29.7, 30.4, 34.5, 35.5, 37.1, 38.1, 38.2, 41.5, 42.5,42.8, 43.2, 47.6, 49.3, 50.1, 50.5, 54.0, 55.1, 66.4, 110.4, 124.9,129.5, 130.9, 147.4, 149.6, 150.8, 169.6, 171.0.

Example 74 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-(dimethylamino)butanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 26% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 4-(dimethylamino)butyric acid hydrochloride was usedinstead of 3-(dimethylamino)propionic acid hydrochloride in Step 1.LCMS: m/e 643.4 (M+H)⁺, 4.19 min (method 8). ¹H NMR (500 MHz,METHANOL-d₄) δ=7.95 (d, J=8.2 Hz, 2H), 7.24 (d, J=8.5 Hz, 2H), 5.33 (dd,J=1.7, 6.3 Hz, 1H), 4.80 (d, J=1.5 Hz, 1H), 4.67 (s, 1H), 3.21-3.14 (m,2H), 2.93 (s, 6H), 2.82-2.67 (m, 2H), 2.49 (t, J=6.9 Hz, 2H), 2.41 (dd,J=8.2, 12.2 Hz, 1H), 2.18 (dd, J=6.4, 17.1 Hz, 1H), 2.06-1.96 (m, 3H),1.96-1.86 (m, 1H), 1.85-1.79 (m, 1H), 1.77 (br. s., 1H), 1.75 (s, 3H),1.73-1.69 (m, 1H), 1.64-1.56 (m, 3H), 1.55-1.48 (m, 4H), 1.47-1.38 (m,3H), 1.35 (d, J=12.2 Hz, 1H), 1.33-1.27 (m, 1H), 1.21-1.17 (m, 1H), 1.15(s, 3H), 1.12 (d, J=3.4 Hz, 1H), 1.07 (s, 6H), 0.99 (s, 3H), 0.97 (s,3H).

Example 75 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(1-methyl-1H-imidazol-2-yl)propanamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 29% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 3-(1-methyl-1H-imidazol-2-yl)propanoic acid was usedinstead of 3-(dimethylamino)propionic acid hydrochloride in Step 1.LCMS: m/e 666.4 (M+H)⁺, 4.15 min (method 8). ¹H NMR (500 MHz,METHANOL-d₄) δ=7.95 (d, J=8.5 Hz, 2H), 7.53-7.46 (m, 2H), 7.25 (d, J=8.2Hz, 2H), 5.33 (dd, J=1.8, 6.1 Hz, 1H), 4.79 (d, J=1.5 Hz, 1H), 4.66 (s,1H), 3.91 (s, 3H), 3.30-3.18 (m, 2H), 2.84-2.79 (m, 2H), 2.73 (dt,J=5.2, 11.1 Hz, 1H), 2.64 (d, J=12.5 Hz, 1H), 2.35 (dd, J=8.2, 12.2 Hz,1H), 2.18 (dd, J=6.4, 17.4 Hz, 1H), 1.96 (dt, J=3.2, 12.1 Hz, 1H),1.91-1.78 (m, 2H), 1.77 (s, 1H), 1.74 (s, 3H), 1.71-1.66 (m, 1H), 1.60(br. s., 2H), 1.46-1.26 (m, 7H), 1.22-1.13 (m, 1H), 1.11 (s, 3H), 1.07(s, 3H), 1.05 (s, 4H), 0.99 (s, 3H), 0.97 (s, 3H).

Example 76 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoacetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 13% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except N,N-dimethyloxamic acid was used instead of3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 627.6(M−H)⁻, 1.91 min (method 5). ¹H NMR (500 MHz, 2:1 MeOD:CDCl₃) δ=7.93 (d,J=8.2 Hz, 2H), 7.55 (s, 1H), 7.21 (d, J=8.2 Hz, 2H), 5.30 (dd, J=1.7,6.3 Hz, 1H), 4.77 (d, J=1.2 Hz, 1H), 4.65 (s, 1H), 3.22 (s, 3H), 3.01(s, 3H), 2.71-2.59 (m, 2H), 2.46 (dd, J=8.2, 11.9 Hz, 1H), 2.14 (dd,J=6.3, 17.2 Hz, 1H), 2.02-1.93 (m, 1H), 1.89 (dt, J=3.4, 12.2 Hz, 1H),1.79 (d, J=13.1 Hz, 1H), 1.75 (d, J=3.7 Hz, 1H), 1.71 (br. s., 1H), 1.66(dt, J=3.5, 13.5 Hz, 1H), 1.61-1.54 (m, 2H), 1.54-1.48 (m, 4H), 1.46(br. s., 1H), 1.45-1.40 (m, 3H), 1.40-1.34 (m, 1H), 1.28 (br. s., 2H),1.20-1.14 (m, 2H), 1.13 (s, 3H), 1.05 (s, 3H), 1.03 (s, 3H), 0.96 (s,3H), 0.95 (s, 3H).

Example 77 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(1H-tetrazol-5-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 8% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except (1H-tetrazol-5-yl)-acetic acid was used instead of3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 640.5(M+H)⁺, 1.58 min (method 6). ¹H NMR (500 MHz, METHANOL-d₄) δ=7.95 (d,J=8.2 Hz, 2H), 7.48 (s, 1H), 7.25 (d, J=8.2 Hz, 2H), 5.33 (dd, J=1.5,6.1 Hz, 1H), 4.82 (d, J=1.8 Hz, 1H), 4.68 (s, 1H), 4.12-4.00 (m, 2H),2.79 (dt, J=5.0, 11.2 Hz, 1H), 2.72-2.62 (m, 1H), 2.45-2.35 (m, 1H),2.19 (dd, J=6.4, 17.1 Hz, 1H), 2.07-1.92 (m, 2H), 1.84 (d, J=11.6 Hz,1H), 1.77 (br. s., 1H), 1.76 (s, 3H), 1.73 (d, J=7.3 Hz, 1H), 1.66-1.56(m, 3H), 1.56-1.49 (m, 4H), 1.48-1.27 (m, 6H), 1.23-1.15 (m, 1H), 1.12(s, 3H), 1.08 (s, 3H), 1.07 (s, 3H), 1.00 (s, 3H), 0.97 (s, 3H).

Example 78 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(1,3,4-thiadiazol-2-ylamino)-2-oxoacetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 21% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-(1,3,4-thiadiazol-2-ylamino)-2-oxoacetic acid was usedinstead of 3-(dimethylamino)propionic acid hydrochloride in Step 1.LCMS: m/e 683.6 (M−H)⁻, 1.77 min (method 9). ¹H NMR (500 MHz, 2:1MeOD:CDCl₃) δ=9.13 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.45 (s, 1H), 7.21(d, J=8.2 Hz, 2H), 5.37-5.24 (m, 1H), 4.81-4.78 (m, 1H), 4.67 (s, 1H),2.67-2.56 (m, 2H), 2.55-2.47 (m, 1H), 2.15 (dd, J=6.4, 17.1 Hz, 1H),1.99-1.90 (m, 1H), 1.82 (dd, J=10.5, 16.3 Hz, 3H), 1.74 (s, 3H), 1.71(br. s., 1H), 1.59-1.44 (m, 9H), 1.44-1.39 (m, 1H), 1.30-1.24 (m, 1H),1.22-1.14 (m, 2H), 1.10 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H), 0.95 (s,3H), 0.94 (s, 3H).

Example 79 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-oxo-2-(thiazol-2-ylamino)acetamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 23% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-oxo-2-(thiazol-2-ylamino)acetic acid was used instead of3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 684.5(M+H)⁺, 2.04 min (method 9). ¹H NMR (500 MHz, 1:1 MeOD:CDCl₃) δ=7.92 (d,J=8.5 Hz, 2H), 7.54 (d, J=3.7 Hz, 1H), 7.49 (s, 1H), 7.22-7.19 (m, 3H),5.30 (dd, J=1.8, 6.1 Hz, 1H), 4.79 (d, J=1.2 Hz, 1H), 2.65-2.55 (m, 2H),2.53-2.46 (m, 1H), 2.14 (dd, J=6.4, 17.1 Hz, 1H), 1.98-1.89 (m, 1H),1.88-1.76 (m, 3H), 1.73 (s, 3H), 1.70 (s, 1H), 1.61-1.36 (m, 11H),1.29-1.22 (m, 1H), 1.21-1.14 (m, 2H), 1.09 (s, 3H), 1.06 (s, 3H), 1.02(s, 3H), 0.95-0.94 (m, 3H), 0.93 (s, 3H).

Example 80 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(cyclohexylamino)-2-oxoacetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 40% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-(cyclohexylamino)-2-oxoacetic acid was used instead of3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 681.7(M−H)⁻, 2.42 min (method 9). ¹H NMR (500 MHz, CHLOROFORM-d) δ=8.03 (d,J=8.5 Hz, 2H), 7.61 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.2 Hz,2H), 6.51 (br. s., 1H), 5.33 (d, J=4.6 Hz, 1H), 4.79 (d, J=1.2 Hz, 1H),4.67 (s, 1H), 3.83-3.72 (m, 1H), 2.62-2.54 (m, 2H), 2.50 (dd, J=8.5,11.6 Hz, 1H), 2.14 (dd, J=6.3, 17.2 Hz, 1H), 2.00-1.89 (m, 3H),1.86-1.75 (m, 4H), 1.71-1.62 (m, 2H), 1.61-1.36 (m, 13H), 1.35-1.20 (m,5H), 1.18-1.11 (m, 2H), 1.08 (s, 3H), 1.05-1.02 (m, 3H), 1.00 (s, 3H),0.96 (s, 6H).

Example 81 Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[3-(1,1-dioxido-4-thiomorpholinyl)-1-oxopropyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]

The title compound was prepared in 70% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 3-(1,1-dioxo-1lamda-6,4-thiazinan-4-yl)propanoic acid wasused instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1.LCMS: m/e 719.5 (M+H)⁺, 1.88 min (method 6). ¹H NMR (500 MHz, 2:1MeOD:CDCl₃) δ=7.93 (d, J=7.9 Hz, 2H), 7.25 (br. s., 1H), 7.21 (d, J=7.9Hz, 2H), 5.30 (d, J=6.1 Hz, 1H), 4.78 (s, 1H), 4.66 (s, 1H), 3.47 (br.s., 4H), 3.36 (br. s., 4H), 3.19 (br. s., 2H), 2.72-2.59 (m, 4H), 2.40(dd, J=8.9, 11.9 Hz, 1H), 2.15 (dd, J=6.3, 17.2 Hz, 1H), 1.98-1.86 (m,2H), 1.80 (d, J=13.1 Hz, 1H), 1.73 (s, 3H), 1.71-1.66 (m, 1H), 1.63-1.43(m, 8H), 1.42-1.23 (m, 5H), 1.22-1.13 (m, 2H), 1.12 (s, 3H), 1.05 (br.s., 3H), 1.04 (br. s., 3H), 0.97 (br. s., 3H), 0.95 (br. s., 3H).

Example 82 Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[(1,1-dioxido-4-thiomorpholinyl)acetyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]

The title compound was prepared in 61% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 4-thiomorpholineacetic acid 1,1-dioxide was used instead of3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 704.5(M+H)⁺, 1.90 min (method 6). ¹H NMR (500 MHz, 2:1 MeOD:CDCl₃) δ=7.93 (d,J=8.2 Hz, 2H), 7.23 (br. s., 1H), 7.21 (s, 2H), 5.31 (dd, J=1.7, 6.0 Hz,1H), 4.78 (d, J=1.2 Hz, 1H), 4.67 (s, 1H), 3.29 (d, J=5.2 Hz, 4H), 3.24(d, J=5.2 Hz, 4H), 2.67-2.60 (m, 1H), 2.53 (dt, J=5.5, 10.8 Hz, 1H),2.47 (dd, J=8.1, 12.7 Hz, 1H), 2.16 (dd, J=6.3, 17.2 Hz, 1H), 1.94-1.78(m, 3H), 1.76 (d, J=2.1 Hz, 1H), 1.74 (s, 3H), 1.62-1.49 (m, 7H),1.47-1.33 (m, 4H), 1.31-1.25 (m, 1H), 1.21-1.13 (m, 2H), 1.12 (s, 3H),1.07 (s, 3H), 1.05 (s, 3H), 0.97 (s, 3H), 0.96 (s, 3H).

Example 83 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-((2S,6R)-2,6-dimethylmorpholino)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 43% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except [(2R,6S)-2,6-dimethylmorpholin-4-yl]acetic acid was usedinstead of 3-(dimethylamino)propionic acid hydrochloride in Step 1.LCMS: m/e 685.6 (M+H)⁺, 2.48 min (method 6). ¹H NMR (500 MHz, 1:1CDCl₃:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H), 5.29 (dd,J=1.5, 6.1 Hz, 1H), 4.75 (d, J=1.2 Hz, 1H), 3.89 (dd, J=6.3, 9.0 Hz,2H), 3.64 (br. s., 1H), 3.24 (br. s., 2H), 2.69-2.49 (m, 4H), 2.39 (dd,J=8.1, 12.4 Hz, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.93-1.76 (m, 3H),1.74 (br. s., 1H), 1.72 (s, 3H), 1.70-1.66 (m, 1H), 1.60-1.42 (m, 8H),1.42-1.30 (m, 3H), 1.25 (d, J=3.1 Hz, 3H), 1.24 (d, J=2.7 Hz, 3H),1.18-1.11 (m, 2H), 1.08 (s, 3H), 1.03 (s, 3H), 1.01 (s, 3H), 0.95 (s,3H), 0.94 (s, 3H).

Example 84 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 23% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except [4-(2-hydroxy-ethyl)-piperazine-1-yl]-acetic aciddihydrochloride was used instead of 3-(dimethylamino)propionic acidhydrochloride in Step 1. LCMS: m/e 700.6 (M+H)⁺, 2.03 min (method 6). ¹HNMR (500 MHz, 1:1 CDCl₃:MeOD) δ=7.92 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.5Hz, 2H), 6.96 (s, 1H), 5.30 (dd, J=1.7, 6.0 Hz, 1H), 4.76 (s, 1H), 4.66(s, 1H), 3.93-3.89 (m, 2H), 3.42 (br. s., 2H), 3.30-3.25 (m, 2H), 3.22(d, J=4.6 Hz, 2H), 2.97 (br. s., 3H), 2.68-2.60 (m, 1H), 2.55-2.47 (m,1H), 2.44 (dd, J=8.2, 12.5 Hz, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H),1.91-1.77 (m, 2H), 1.75 (br. s., 1H), 1.72 (s, 3H), 1.72-1.68 (m, 1H),1.62-1.31 (m, 11H), 1.30-1.24 (m, 1H), 1.15 (d, J=13.1 Hz, 2H), 1.08 (s,3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H).

Example 85 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(4-ethylpiperazin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 34% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-(4-ethylpiperazin-1-yl)acetic acid was used instead of3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 684.6(M+H)⁺, 2.35 min (method 6). ¹H NMR (500 MHz, 1:1 CDCl₃:MeOD) δ=7.92 (d,J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H), 6.90 (s, 1H), 5.29 (d, J=6.1 Hz,1H), 4.75 (d, J=1.2 Hz, 1H), 3.27-3.14 (m, 5H), 2.96 (br. s., 3H), 2.64(d, J=13.4 Hz, 1H), 2.55-2.38 (m, 2H), 2.13 (dd, J=6.4, 17.1 Hz, 1H),1.92-1.76 (m, 2H), 1.74 (br. s., 1H), 1.72 (s, 3H), 1.70-1.67 (m, 1H),1.61-1.41 (m, 9H), 1.37 (t, J=7.3 Hz, 4H), 1.35-1.31 (m, 1H), 1.29-1.23(m, 1H), 1.18-1.12 (m, 2H), 1.06 (s, 3H), 1.03 (s, 3H), 1.01 (s, 2H),0.94 (s, 3H), 0.94 (s, 3H).

Example 86 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-((2-methoxyethyl)(methyl)amino)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 38% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except N-(2-methoxyethyl)-N-methylglycine was used instead of3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 659.6(M+H)⁺, 2.41 min (method 6). ¹H NMR (500 MHz, 1:1 CDCl₃:MeOD) δ=7.92 (d,J=7.9 Hz, 2H), 7.43 (s, 1H), 7.20 (d, J=8.2 Hz, 2H), 5.29 (d, J=5.8 Hz,1H), 4.75 (s, 1H), 3.96 (br. s., 2H), 3.73 (t, J=4.7 Hz, 2H), 3.42 (s,3H), 3.40 (br. s., 2H), 2.94 (s, 3H), 2.73-2.61 (m, 2H), 2.36 (dd,J=8.4, 12.1 Hz, 1H), 2.12 (dd, J=6.1, 17.1 Hz, 1H), 1.88 (t, J=11.6 Hz,2H), 1.77 (d, J=11.6 Hz, 1H), 1.73 (br. s., 1H), 1.71 (s, 3H), 1.70-1.65(m, 1H), 1.58-1.30 (m, 11H), 1.25 (d, J=6.1 Hz, 1H), 1.18-1.10 (m, 2H),1.09 (s, 3H), 1.02 (s, 3H), 1.01 (s, 3H), 0.94 (br. s., 3H), 0.93 (br.s., 3H).

Example 87 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(4-phenyl-1H-pyrazol-1-yl)acetamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 22% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-(3-phenyl-1H-pyrazol-1-yl)acetic acid was used instead of3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 714.6(M+H)⁺, 2.59 min (method 6). ¹H NMR (500 MHz, 1:1 CDCl₃:MeOD) δ=7.91 (d,J=8.2 Hz, 4H), 7.67 (d, J=2.1 Hz, 1H), 7.42 (d, J=7.3 Hz, 2H), 7.40 (s,1H), 7.37-7.31 (m, 1H), 7.18 (d, J=7.9 Hz, 2H), 5.24 (d, J=4.6 Hz, 1H),4.86-4.75 (m, 2H), 4.59 (s, 1H), 3.37 (s, 3H), 2.50 (dd, J=2.4, 9.2 Hz,1H), 2.47-2.38 (m, 2H), 1.97 (dd, J=6.4, 17.1 Hz, 1H), 1.93-1.83 (m,1H), 1.64 (s, 3H), 1.60-1.52 (m, 2H), 1.50-1.37 (m, 4H), 1.37-1.27 (m,7H), 1.26-1.19 (m, 1H), 1.16-1.11 (m, 1H), 1.00 (dd, J=2.4, 9.2 Hz, 1H),0.90 (s, 3H), 0.89 (s, 6H), 0.79 (s, 3H), 0.61 (s, 3H), 0.49 (dd, J=4.3,13.1 Hz, 1H).

Example 88 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(1H-1,2,3-triazol-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 36% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 1H-1,2,3-triazole-1-acetic acid hydrochloride was usedinstead of 3-(dimethylamino)propionic acid hydrochloride in Step 1.LCMS: m/e 639.5 (M+H)⁺, 2.04 min (method 6). ¹H NMR (500 MHz, 1:1CDCl₃:MeOD) δ=7.94 (d, J=0.9 Hz, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.77 (d,J=0.9 Hz, 1H), 7.20 (d, J=8.5 Hz, 2H), 6.93 (s, 1H), 5.29 (dd, J=1.7,6.3 Hz, 1H), 5.15 (s, 2H), 4.75 (d, J=1.5 Hz, 1H), 4.64 (br. s., 1H),2.63-2.57 (m, 1H), 2.57-2.50 (m, 1H), 2.37 (dd, J=8.1, 12.7 Hz, 1H),2.12 (dd, J=6.4, 17.1 Hz, 1H), 1.94-1.83 (m, 1H), 1.78-1.72 (m, 3H),1.70 (s, 3H), 1.69-1.64 (m, 1H), 1.58-1.39 (m, 8H), 1.38-1.29 (m, 3H),1.24 (dd, J=3.7, 10.4 Hz, 1H), 1.15-1.06 (m, 2H), 1.02 (s, 3H), 1.01 (s,3H), 1.00 (s, 3H), 0.94 (s, 3H), 0.93 (s, 3H).

Example 89 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(1H-imidazol-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 60% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except imidazol-1-ylacetic acid was used instead of3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 638.5(M+H)⁺, 2.05 min (method 6). ¹H NMR (400 MHz, 1:1 CDCl₃:MeOD) δ=8.88 (s,1H), 7.92 (d, J=8.3 Hz, 2H), 7.47 (ddd, J=1.6, 1.8, 9.7 Hz, 2H), 7.42(s, 1H), 7.20 (d, J=8.5 Hz, 2H), 5.33-5.25 (m, 1H), 5.02 (d, J=5.0 Hz,2H), 4.78 (d, J=1.3 Hz, 1H), 4.65 (d, J=1.8 Hz, 2H), 2.72 (dt, J=5.3,11.0 Hz, 1H), 2.66-2.57 (m, 1H), 2.33 (dd, J=8.2, 12.7 Hz, 1H), 2.13(dd, J=6.3, 17.1 Hz, 1H), 2.00-1.88 (m, 2H), 1.80 (d, J=14.6 Hz, 1H),1.74 (br. s., 1H), 1.72 (s, 3H), 1.71-1.67 (m, 1H), 1.60-1.32 (m, 11H),1.30-1.22 (m, 1H), 1.19-1.13 (m, 1H), 1.12 (s, 3H), 1.03 (s, 3H), 1.02(s, 2H), 0.95 (s, 3H), 0.94 (br. s., 3H).

Example 90 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(1H-indol-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 31% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-(1H-indol-1-yl)acetic acid was used instead of3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 687.6(M+H)⁺, 2.60 min (method 6). ¹H NMR (400 MHz, 1:1 CDCl₃:MeOD) δ=7.92 (d,J=8.5 Hz, 2H), 7.72 (d, J=7.8 Hz, 1H), 7.40-7.35 (m, 1H), 7.32-7.25 (m,1H), 7.24-7.16 (m, 4H), 6.71 (dd, J=0.8, 3.3 Hz, 1H), 5.27 (dd, J=1.6,6.1 Hz, 1H), 4.90 (s, 1H), 4.83 (s, 2H), 4.44 (s, 1H), 4.33 (d, J=1.8Hz, 1H), 2.48 (d, J=12.5 Hz, 1H), 2.39-2.31 (m, 1H), 2.08 (dd, J=6.4,17.2 Hz, 1H), 1.64 (d, J=16.6 Hz, 1H), 1.54 (d, J=8.0 Hz, 2H), 1.50 (s,3H), 1.39 (br. s., 3H), 1.37-1.23 (m, 6H), 1.23-1.13 (m, 4H), 1.04 (br.s., 1H), 1.00 (s, 4H), 0.95 (s, 3H), 0.92 (s, 3H), 0.87 (s, 3H), 0.82(s, 3H).

Example 91 (Isomer 1) and Example 92 (Isomer 2) Preparation of benzoicacid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[(1,1-dioxido-4-thiomorpholinyl)phenylacetyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]

The title compounds were prepared in 21% and 11% yield, respectively,from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-(1,1-dioxo-1-lamda-6-4-thiazinan-4-yl)-2-phenylaceticacid was used instead of 3-(dimethylamino)propionic acid hydrochloridein Step 1. The two isomers formed in the reaction were separated byreverse phase preparative HPLC.

Isomer 1: LCMS: m/e 781.6 (M+H)⁺, 2.21 min (method 6). ¹H NMR (400 MHz,1:1 CDCl₃:MeOD) δ=7.92 (d, J=8.5 Hz, 2H), 7.49-7.44 (m, 2H), 7.43-7.36(m, 3H), 7.20 (d, J=8.3 Hz, 2H), 6.62 (s, 1H), 5.29 (dd, J=1.6, 6.1 Hz,1H), 4.76 (d, J=1.3 Hz, 1H), 4.64 (br. s., 1H), 4.26 (s, 1H), 3.19-3.13(m, 4H), 3.12-3.01 (m, 4H), 2.57-2.48 (m, 2H), 2.40 (dd, J=8.0, 11.8 Hz,1H), 2.12 (dd, J=6.3, 17.1 Hz, 1H), 1.76 (d, J=14.6 Hz, 1H), 1.71 (br.s., 1H), 1.70 (s, 3H), 1.66 (d, J=11.0 Hz, 3H), 1.50 (d, J=16.3 Hz, 3H),1.46-1.38 (m, 3H), 1.38-1.09 (m, 9H), 1.00 (s, 3H), 0.97 (s, 3H), 0.94(s, 3H), 0.92 (s, 3H), 0.84 (s, 3H).

Isomer 2: LCMS: m/e 781.6 (M+H)⁺, 2.22 min (method 6). ¹H NMR (400 MHz,1:1 CDCl₃:MeOD) δ=7.92 (d, J=8.3 Hz, 2H), 7.49-7.44 (m, 2H), 7.43-7.34(m, 3H), 7.21 (d, J=8.3 Hz, 2H), 6.64 (s, 1H), 5.30 (dd, J=1.6, 6.1 Hz,1H), 4.75 (s, 1H), 4.65 (s, 1H), 4.16 (s, 1H), 3.25-2.99 (m, 8H),2.65-2.57 (m, 1H), 2.42 (dt, J=5.6, 10.9 Hz, 1H), 2.32 (dd, J=8.3, 12.5Hz, 1H), 2.15 (dd, J=6.4, 16.9 Hz, 1H), 1.85-1.72 (m, 3H), 1.70 (s, 3H),1.61-1.23 (m, 14H), 1.10 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H), 0.96 (s,3H), 0.94 (s, 3H).

Example 93 Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxido-4-thiomorpholinyl)-1-oxopropyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]

The title compound was prepared in 44% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-(1,1-dioxidothiomorpholin-4-yl)-propionic acid was usedinstead of 3-(dimethylamino)propionic acid hydrochloride in Step 1.LCMS: m/e 719.5 (M+H)⁺, 2.03 min (method 6). ¹H NMR (500 MHz, 1:1CDCl₃:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.54 (s, 1H), 7.20 (d, J=7.9 Hz,2H), 5.29 (d, J=5.2 Hz, 1H), 4.75 (d, J=10.4 Hz, 1H), 4.66 (br. s., 1H),3.48-3.39 (m, 1H), 3.28-3.11 (m, 8H), 2.69-2.55 (m, 1H), 2.50-2.34 (m,2H), 2.13 (dd, J=6.1, 17.1 Hz, 1H), 1.80 (d, J=11.6 Hz, 2H), 1.72 (s,6H), 1.59-1.44 (m, 8H), 1.43-1.36 (m, 2H), 1.33 (dd, J=6.9, 14.8 Hz,4H), 1.25 (d, J=6.7 Hz, 1H), 1.15 (d, J=11.0 Hz, 2H), 1.08 (s, 3H), 1.03(s, 3H), 1.01 (s, 3H), 0.94 (br. s., 6H).

Example 94 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(3,3-difluoroazetidin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(3,3-difluoroazetidin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-bromoacetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(129 mg, 0.194 mmol) in THF (3 mL) was added N,N-diisopropylethylamine(0.338 mL, 1.941 mmol) and 3,3-difluoroazetidine, HCl (126 mg, 0.970mmol). The reaction mixture was stirred at 160° C. for 5 h. The mixturewas concentrated and the crude residue was dissolved in THF (1.5 mL),filtered and purified by reverse phase preparative HPLC using Prep HPLCmethod 3 to give methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(3,3-difluoroazetidin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(28.8 mg, 0.043 mmol, 21.9% yield) as brown solid. LC/MS: m/e 677.5(M+H)⁺, 2.93 min (method 6).

Step 2. Preparation of give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(3,3-difluoroazetidin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(3,3-difluoroazetidin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(28.8 mg, 0.043 mmol) in THF (Volume: 3 mL) was added a 0.753 molarsolution of Li.HO.H₂O (0.340 mL, 0.170 mmol) in H₂O. The reaction washeated to 75° C. for 6 h and was then concentrated to a brown viscousoil. The crude residue was dissolved in THF (1.3 mL) and 0.2 mL 1N HCl,filtered and purified by reverse phase preparative HPLC using prep HPLCmethod 3 to give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(3,3-difluoroazetidin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA (17.6 mg, 0.022 mmol, 52.7% yield) as a light yellow solid.LCMS: m/e 663.7 (M+H)⁺, 2.22 min (method 2). ¹H NMR (500 MHz, 1:1CDCl₃:METHANOL-d₄) δ 7.90 (d, J=8.2 Hz, 2H), 7.18 (d, J=8.2 Hz, 2H),5.27 (d, J=4.6 Hz, 1H), 4.73 (s, 1H), 3.88 (t, J=12.5 Hz, 2H), 3.69-3.59(m, 1H), 3.55-3.39 (m, 3H), 2.64-2.53 (m, 2H), 2.39 (dd, J=12.2, 8.2 Hz,1H), 2.10 (dd, J=17.1, 6.4 Hz, 1H), 1.93-1.73 (m, 3H), 1.69 (s, 3H),1.67 (d, J=4.6 Hz, 1H), 1.58-1.39 (m, 8H), 1.39-1.29 (m, 3H), 1.23 (d,J=10.1 Hz, 1H), 1.11 (d, J=13.7 Hz, 2H), 1.06 (s, 3H), 1.00 (s, 3H),0.99 (s, 3H), 0.92 (br. s., 3H), 0.91 (br. s., 3H).

Example 95 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(2-oxopyrrolidin-1-yl)acetamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 14% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-(2-oxopyrrolidin-1-yl)acetic acid was used instead of3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 655.5(M+H)⁺, 1.99 min (method 6). ¹H NMR (500 MHz, 1:1 CDCl₃:MeOD) δ=7.92 (d,J=7.9 Hz, 2H), 7.20 (d, J=7.9 Hz, 2H), 6.77 (s, 1H), 5.29 (d, J=4.7 Hz,1H), 4.75 (d, J=1.3 Hz, 1H), 4.63 (s, 1H), 3.97-3.85 (m, 2H), 3.58-3.51(m, 2H), 2.65-2.54 (m, 2H), 2.47 (t, J=8.0 Hz, 2H), 2.38 (dd, J=8.4,12.5 Hz, 1H), 2.17-2.07 (m, 3H), 1.95-1.85 (m, 1H), 1.83-1.74 (m, 2H),1.73 (br. s., 1H), 1.70 (s, 3H), 1.68-1.62 (m, 1H), 1.60-1.43 (m, 8H),1.42-1.22 (m, 6H), 1.13 (br. s., 1H), 1.09 (s, 3H), 1.01 (s, 6H), 0.94(s, 3H), 0.93 (s, 3H).

Example 96 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(4-isopropylpiperazin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 22% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except (4-isopropyl-piperazin-1-yl)-acetic acid was used insteadof 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e698.6 (M+H)⁺, 2.64 min (method 6). ¹H NMR (500 MHz, 1:1 CDCl₃:MeOD)δ=7.92 (d, J=8.2 Hz, 2H), 7.37 (br. s., 1H), 7.20 (d, J=8.2 Hz, 2H),6.34-6.03 (m, 1H), 5.29 (d, J=4.6 Hz, 1H), 4.76 (br. s., 1H), 4.70 (br.s., 1H), 3.95 (br. s., 1H), 3.84-3.55 (m, 8H), 3.17 (q, J=7.2 Hz, 2H),2.64 (d, J=13.1 Hz, 2H), 2.39 (dd, J=8.1, 11.4 Hz, 1H), 2.12 (dd, J=6.3,17.2 Hz, 1H), 1.96-1.84 (m, 2H), 1.79 (d, J=12.5 Hz, 1H), 1.76-1.65 (m,5H), 1.59-1.40 (m, 14H), 1.35 (t, J=7.2 Hz, 4H), 1.29-1.21 (m, 1H), 1.15(d, J=6.1 Hz, 1H), 1.10 (br. s., 3H), 1.02 (s, 3H), 1.01 (br. s., 2H),0.94 (br. s., 3H), 0.93 (br. s., 3H).

Example 97 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoacetamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 40% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except morpholin-4-yl-acetic acid was used instead of3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 657.6(M+H)⁺, 2.20 min (method 6). ¹H NMR (500 MHz, 1:1 CDCl₃:MeOD) δ=7.91 (d,J=7.9 Hz, 2H), 7.48 (br. s., 1H), 7.19 (d, J=8.2 Hz, 2H), 5.28 (d, J=4.9Hz, 1H), 4.77 (br. s., 1H), 4.12-3.79 (m, 6H), 3.57-3.40 (m, 2H),3.22-3.11 (m, 1H), 2.74 (br. s., 1H), 2.65 (d, J=12.8 Hz, 1H), 2.42-2.29(m, 1H), 2.12 (dd, J=6.1, 17.1 Hz, 1H), 2.03-1.85 (m, 2H), 1.79 (d,J=12.8 Hz, 1H), 1.72 (br. s., 1H), 1.71 (s, 3H), 1.69 (br. s., 1H),1.60-1.30 (m, 12H), 1.24 (d, J=5.8 Hz, 1H), 1.14 (br. s., 1H), 1.10 (br.s., 4H), 1.02 (br. s., 3H), 1.00 (br. s., 3H), 0.93 (br. s., 3H), 0.92(br. s., 3H).

Example 98 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-thiomorpholinoacetamido)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 44% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-thiomorpholinoacetic acid was used instead of3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 671.8(M−H)⁻, 2.37 min (method 6). ¹H NMR (500 MHz, 1:1 CDCl₃:MeOD) δ=7.92 (d,J=8.2 Hz, 2H), 7.47 (s, 1H), 7.20 (d, J=8.2 Hz, 2H), 5.29 (d, J=4.3 Hz,1H), 4.75 (s, 1H), 3.79-3.63 (m, 2H), 3.58 (td, J=6.5, 12.9 Hz, 1H),3.47-3.35 (m, 3H), 2.95 (br. s., 4H), 2.68-2.57 (m, 2H), 2.37 (dd,J=8.4, 12.4 Hz, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.92-1.82 (m, 2H),1.81-1.76 (m, 1H), 1.73 (br. s., 1H), 1.71 (s, 3H), 1.69-1.64 (m, 1H),1.60-1.31 (m, 12H), 1.30-1.22 (m, 1H), 1.19-1.11 (m, 2H), 1.09 (s, 3H),1.03 (s, 3H), 1.01 (s, 3H), 0.94 (br. s., 3H), 0.93 (br. s., 3H).

Example 99 Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[3-cyclohexyl-2-(1,1-dioxido-4-thiomorpholinyl)-1-oxopropyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]

The title compound was prepared in 23% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except3-cyclohexyl-2-(1,1-dioxo-1lambda6,-4,thiazinan-4-yl)propanoic acid wasused instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1.LCMS: m/e 801.6 (M+H)⁺, 2.43 min (method 6). ¹H NMR (500 MHz, 1:1CDCl₃:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H), 6.56 (s,1H), 5.29 (d, J=4.6 Hz, 1H), 4.76 (s, 1H), 3.58 (td, J=6.6, 13.4 Hz,1H), 3.44 (dd, J=5.0, 9.6 Hz, 1H), 3.30-3.25 (m, 3H), 3.24-3.15 (m, 2H),3.14-3.06 (m, 2H), 2.68 (d, J=13.4 Hz, 1H), 2.56 (dt, J=5.6, 11.1 Hz,1H), 2.41 (dd, J=8.4, 12.7 Hz, 1H), 2.13 (dd, J=6.3, 17.2 Hz, 1H),1.92-1.75 (m, 5H), 1.73 (br. s., 1H), 1.72 (s, 3H), 1.70-1.64 (m, 4H),1.61-1.40 (m, 10H), 1.40-1.29 (m, 3H), 1.28-1.11 (m, 7H), 1.09 (s, 3H),1.03 (s, 3H), 1.01 (s, 3H), 0.97 (d, J=3.1 Hz, 1H), 0.94 (br. s., 3H),0.93 (br. s., 3H).

Example 100 Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-3a-[[[methyl(tetrahydro-1,1-dioxido-3-thienyl)amino]acetyl]amino]-1H-cyclopenta[a]chrysen-9-yl]

The title compound was prepared in 17% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except N-(1,1-dioxidotetrahydro-3-thienyl)-N-methylglycine wasused instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1.LCMS: m/e 719.5 (M+H)⁺, 2.00 min (method 6). ¹H NMR (500 MHz,CDCl₃:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.30 (d, J=7.6 Hz, 1H), 7.20 (d,J=8.2

Hz, 2H), 5.29 (d, J=4.9 Hz, 1H), 3.80 (br. s., 1H), 3.40 (dd, J=7.6,13.4 Hz, 1H), 3.30-3.05 (m, 4H), 2.60 (br. s., 1H), 2.57 (d, J=1.5 Hz,3H), 2.55-2.41 (m, 3H), 2.23 (quin, J=10.6 Hz, 1H), 2.13 (dd, J=6.1,17.1 Hz, 1H), 1.91-1.76 (m, 2H), 1.73 (br. s., 1H), 1.71 (s, 3H), 1.70(br. s., 1H), 1.60-1.29 (m, 12H), 1.25 (d, J=7.0 Hz, 1H), 1.21-1.11 (m,3H), 1.09 (s, 3H), 1.03 (s, 3H), 1.01 (s, 3H), 0.94 (s, 3

H), 0.93 (br. s., 3H).

Example 101 Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[3-(1,1-dioxido-4-thiomorpholinyl)-1-oxo-3-(2-thienyl)propyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl

The title compound was prepared in 39% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except3-(1,1-dioxo-1lambda-6,4-thiazinan-4-yl)-3-(2-thienyl)propanoic acid wasused instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1.LCMS: m/e 801.6 (M+H)⁺, 2.16 min (method 6). ¹H NMR (500 MHz, 1:1CDCl₃:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.36-7.28 (m, 1H), 7.20 (d, J=8.2Hz, 2H), 7.05-6.91 (m, 2H), 6.59 (s, 1H), 5.29 (d, J=4.9 Hz, 1H), 4.74(d, J=7.6 Hz, 1H), 4.60-4.52 (m, 2H), 3.18-3.05 (m, 6H), 3.04-2.93 (m,2H), 2.91-2.72 (m, 2H), 2.68-2.49 (m, 2H), 2.48-2.40 (m, 1H), 2.27 (dd,J=8.5, 11.9 Hz, 1H), 2.12 (dd, J=4.9, 17.1 Hz, 1H), 1.93-1.72 (m, 3H),1.69 (d, J=7.9 Hz, 3H), 1.64 (d, J=11.6 Hz, 1H), 1.61-1.38 (m, 8H),1.37-1.19 (m, 5H), 1.13 (br. s., 1H), 1.11 (br. s., 15H), 1.10 (br. s.,2H), 1.02 (br. s., 1H), 1.01 (br. s., 2H), 1.01 (br. s., 1H), 1.00 (br.s., 2H), 0.95 (br. s., 1H), 0.95 (br. s., 2H), 0.93 (s, 3H).

Example 102 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyrazin-2-yl)acetamido)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 14% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-pyrazine acetic acid was used instead of3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 650.6(M+H)⁺, 2.12 min (method 6). ¹H NMR (500 MHz, 1:1 CDCl₃:MeOD)δ=8.68-8.50 (m, 3H), 7.92 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 3H),5.29 (dd, J=1.7, 6.0 Hz, 1H), 4.76 (s, 1H), 3.79 (q, J=14.3 Hz, 2H),2.66-2.53 (m, 2H), 2.42-2.31 (m, 1H), 2.12 (dd, J=6.4, 17.1 Hz, 1H),1.91-1.74 (m, 3H), 1.72 (br. s., 1H), 1.71 (s, 2H), 1.67 (d, J=11.9 Hz,2H), 1.57-1.18 (m, 13H), 1.17-1.02 (m, 3H), 1.00 (br. s., 3H), 1.00 (br.s., 3H), 0.94 (s, 3H), 0.92 (br. s., 3H), 0.92 (br. s., 3H).

Example 103 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(1H-tetrazol-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 33% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 1-H-tetrazole-1-acetic acid was used instead of3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 638.7(M−H)⁻, 1.98 min (method 6). ¹H NMR (500 MHz, 1:1 CDCl₃:MeOD) δ=9.10 (s,1H), 7.93 (d, J=8.2 Hz, 2H), 7.39 (s, 1H), 7.21 (d, J=8.2 Hz, 2H), 5.30(dd, J=1.5, 6.1 Hz, 1H), 5.27 (d, J=1.5 Hz, 2H), 4.78 (d, J=1.2 Hz, 1H),4.65 (s, 1H), 2.71 (dt, J=5.2, 11.1 Hz, 1H), 2.64-2.56 (m, 1H), 2.34(dd, J=8.1, 12.7 Hz, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 2.00-1.86 (m,2H), 1.80 (d, J=11.0 Hz, 1H), 1.74 (br. s., 1H), 1.72 (s, 3H), 1.71-1.66(m, 1H), 1.62-1.30 (m, 11H), 1.29-1.22 (m, 1H), 1.20-1.14 (m, 1H), 1.12(s, 3H), 1.10 (d, J=4.3 Hz, 1H), 1.03 (s, 6H), 0.95 (s, 3H), 0.94 (s,3H).

Example 104 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(7-chloro-2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 36% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-(6-chloro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)aceticacid was used instead of 3-(dimethylamino)propionic acid hydrochloridein Step 1. LCMS: m/e 653.5 (M+H)⁺, 2.29 min (method 6). ¹H NMR (500 MHz,1:1 CDCl₃:MeOD) δ=7.92 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H),7.05-7.01 (m, 1H), 7.01-6.97 (m, 2H), 6.83 (s, 1H), 5.29 (dd, J=1.7, 6.3Hz, 1H), 4.73 (d, J=1.8 Hz, 1H), 4.70 (d, J=1.2 Hz, 2H), 4.66 (br. s.,1H), 4.63 (s, 1H), 4.57-4.50 (m, 1H), 2.65-2.57 (m, 1H), 2.51-2.34 (m,2H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.96-1.85 (m, 1H), 1.83-1.72 (m,3H), 1.70 (s, 3H), 1.69-1.64 (m, 1H), 1.63-1.55 (m, 2H), 1.54-1.45 (m,4H), 1.45-1.30 (m, 5H), 1.30-1.23 (m, 1H), 1.18-1.12 (m, 2H), 1.10 (s,3H), 1.02 (s, 6H), 0.95 (s, 3H), 0.94 (s, 3H).

Example 105 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(2-oxooxazolidin-3-yl)acetamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 29% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-(2-oxooxazolidin-3-yl)acetic acid was used instead of3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 657.5(M+H)⁺, 1.97 min (method 6). ¹H NMR (500 MHz, 1:1 CDCl₃:MeOD) δ=7.92 (d,J=8.2 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 6.82 (s, 1H), 5.29 (dd, J=1.7,6.3 Hz, 1H), 4.76 (d, J=1.5 Hz, 1H), 4.64 (s, 2H), 4.43 (dt, J=1.7, 8.2Hz, 2H), 3.98-3.84 (m, 2H), 3.74 (t, J=8.1 Hz, 2H), 2.69-2.56 (m, 2H),2.40 (dd, J=8.1, 12.4 Hz, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.98-1.81(m, 2H), 1.81-1.75 (m, 1H), 1.73 (br. s., 1H), 1.71 (s, 3H), 1.70-1.65(m, 1H), 1.61-1.43 (m, 7H), 1.42-1.29 (m, 4H), 1.29-1.21 (m, 2H),1.16-1.12 (m, 1H), 1.10 (s, 3H), 1.02 (s, 3H), 1.02 (s, 3H), 0.95 (s,3H), 0.94 (s, 3H).

Example 106 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-hydroxyethylamino)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 14% yield as a by-product during theabove described preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(2-oxooxazolidin-3-yl)acetamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid. LCMS: m/e 631.5 (M+H)⁺, 1.94 min (method 6). ¹H NMR (500 MHz, 1:1CDCl₃:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H), 5.29 (d,J=4.6 Hz, 1H), 4.76 (s, 1H), 4.65 (s, 1H), 3.87-3.75 (m, 4H), 3.17-3.12(m, 2H), 2.73-2.62 (m, 2H), 2.37 (dd, J=8.4, 12.1 Hz, 1H), 2.13 (dd,J=6.3, 17.2 Hz, 1H), 2.16-2.09 (m, 1H), 1.95-1.85 (m, 2H), 1.79 (d,J=11.0 Hz, 1H), 1.74 (br. s., 1H), 1.72 (s, 3H), 1.71-1.66 (m, 1H),1.58-1.47 (m, 6H), 1.47-1.32 (m, 5H), 1.30-1.23 (m, 1H), 1.16-1.11 (m,2H), 1.10 (s, 3H), 1.03 (s, 3H), 1.02 (s, 3H), 0.95 (s, 3H), 0.94 (br.s., 3H).

Example 107 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-((S)-2-oxo-4-phenyloxazolidin-3-yl)acetamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 30% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except (S)-(+)-2-oxo-4-phenyl-3-oxazolidineacetic acid was usedinstead of 3-(dimethylamino)propionic acid hydrochloride in Step 1.LCMS: m/e 733.5 (M+H)⁺, 2.25 min (method 6). ¹H NMR (400 MHz, 1:1CDCl₃:MeOD) δ=7.92 (d, J=8.3 Hz, 2H), 7.47-7.39 (m, 3H), 7.37-7.32 (m,2H), 7.20 (d, J=8.3 Hz, 2H), 6.60 (s, 1H), 5.28 (d, J=4.5 Hz, 1H), 5.04(t, J=8.3 Hz, 1H), 4.75 (t, J=8.9 Hz, 1H), 4.71 (s, 1H), 4.61 (br. s.,1H), 4.25-4.19 (m, 1H), 4.04 (d, J=16.3 Hz, 1H), 3.40 (d, J=16.3 Hz,1H), 2.65-2.59 (m, 1H), 2.47 (dt, J=4.8, 11.0 Hz, 1H), 2.37 (dd, J=8.2,11.7 Hz, 1H), 2.11 (dd, J=6.3, 17.1 Hz, 1H), 1.84-1.70 (m, 4H), 1.69 (s,3H), 1.66-1.59 (m, 1H), 1.58-1.40 (m, 7H), 1.39-1.22 (m, 6H), 1.09 (br.s., 1H), 1.07 (s, 3H), 1.00 (s, 6H), 0.95 (s, 3H), 0.94 (br. s., 3H).

Example 108 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-((S)-2-hydroxy-1-phenylethylamino)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 8% yield as a by-product during theabove described preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-((S)-2-oxo-4-phenyloxazolidin-3-yl)acetamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid. LCMS: m/e 707.5 (M+H)⁺, 2.18 min (method 6). ¹H NMR (400 MHz, 1:1CDCl₃:MeOD) δ=7.92 (d, J=8.3 Hz, 2H), 7.49-7.45 (m, 3H), 7.45-7.40 (m,2H), 7.19 (d, J=8.3 Hz, 2H), 5.28 (d, J=4.8 Hz, 1H), 4.71 (s, 1H), 4.62(br. s., 2H), 4.35 (dd, J=4.9, 7.7 Hz, 1H), 4.04-3.90 (m, 2H), 3.72-3.55(m, 2H), 2.60-2.50 (m, 2H), 2.36 (dd, J=8.5, 12.0 Hz, 1H), 2.10 (dd,J=6.4, 17.2 Hz, 1H), 1.91-1.75 (m, 2H), 1.73 (d, J=7.3 Hz, 2H), 1.69 (s,3H), 1.65-1.60 (m, 1H), 1.50-1.37 (m, 6H), 1.37-1.19 (m, 7H), 1.07 (d,J=18.6 Hz, 3H), 0.99 (s, 6H), 0.97 (s, 3H), 0.94 (br. s., 3H), 0.94 (br.s., 3H).

Example 109 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-((S)-3-(tert-butoxycarbonylamino)-2-oxopyrrolidin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 34% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except(S)-2-(3-(tert-butoxycarbonylamino)-2-oxopyrrolidin-1-yl)acetic acid wasused instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1.LCMS: m/e 770.6 (M+H)⁺, 2.07 min (method 6). ¹H NMR (400 MHz, 1:1CDCl₃:MeOD) δ=7.92 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 6.83-6.60(m, 1H), 5.29 (d, J=4.8 Hz, 1H), 4.76 (s, 1H), 4.63 (br. s., 1H),4.32-4.16 (m, 1H), 4.07-3.84 (m, 2H), 3.44 (d, J=7.0 Hz, 2H), 2.70-2.56(m, 2H), 2.55-2.44 (m, 1H), 2.43-2.31 (m, 1H), 2.13 (dd, J=6.3, 17.1 Hz,1H), 2.08-1.95 (m, 1H), 1.94-1.82 (m, 2H), 1.81-1.73 (m, 2H), 1.71 (s,3H), 1.68-1.62 (m, 1H), 1.61-1.48 (m, 6H), 1.46 (s, 9H), 1.43-1.22 (m,6H), 1.13 (br. s., 1H), 1.10 (d, J=3.8 Hz, 3H), 1.02 (s, 6H), 0.95 (br.s., 3H), 0.94 (br. s., 3H).

Example 110 (Isomer 1) and Example 111 (Isomer 2) Preparation of benzoicacid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxido-4-thiomorpholinyl)-3-methyl-1-oxobutyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]

The title compounds were prepared in 9% yield each from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-(1,1-dioxo-1-lambda-6,4-thiazinan-4-yl)3-methylbutanoicacid (91 mg, 0.388 mmol) was used instead of 3-(dimethylamino)propionicacid hydrochloride in Step 1. The two isomers formed in the reactionwere separated by reverse phase preparative HPLC.

Isomer 1: LCMS: m/e 747.5 (M+H)⁺, 2.23 min (method 6). ¹H NMR (500 MHz,1:1 CDCl₃:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 6.42(s, 1H), 5.29 (dd, J=1.5, 6.1 Hz, 1H), 4.75 (d, J=1.5 Hz, 1H), 4.64 (br.s., 1H), 3.31-3.23 (m, 2H), 3.16-3.07 (m, 4H), 3.06-2.97 (m, 2H), 2.84(d, J=10.4 Hz, 1H), 2.77-2.71 (m, 1H), 2.63 (dt, J=5.5, 11.1 Hz, 1H),2.42 (dd, J=8.2, 12.5 Hz, 1H), 2.12 (dd, J=6.4, 17.1 Hz, 1H), 2.03 (qd,J=6.5, 16.9 Hz, 1H), 1.91-1.81 (m, 2H), 1.78 (d, J=12.2 Hz, 1H), 1.73(br. s., 1H), 1.71 (s, 3H), 1.68 (d, J=11.3 Hz, 1H), 1.62 (dd, J=3.4,13.4 Hz, 1H), 1.57 (d, J=4.9 Hz, 1H), 1.51 (br. s., 3H), 1.47 (d, J=12.5Hz, 1H), 1.44-1.28 (m, 5H), 1.28-1.23 (m, 2H), 1.18 (d, J=13.7 Hz, 1H),1.11 (dd, J=4.0, 12.8 Hz, 1H), 1.08 (s, 3H), 1.02 (s, 3H), 1.01 (s, 4H),0.99 (s, 2H), 0.94 (s, 3H), 0.94 (br. s., 3H), 0.90 (d, J=6.4 Hz, 3H).

Isomer 2: LCMS: m/e 747.5 (M+H)+, 2.29 min (method 6). ¹H NMR (500 MHz,1:1 CDCl₃:MeOD) δ=7.92 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H), 6.40(s, 1H), 5.29 (dd, J=1.5, 6.1 Hz, 1H), 4.76 (d, J=1.5 Hz, 1H), 4.64 (s,1H), 3.77-3.72 (m, 1H), 3.23-3.14 (m, 2H), 3.13-3.06 (m, 4H), 3.05-2.99(m, 2H), 2.80 (d, J=10.4 Hz, 1H), 2.74-2.67 (m, 1H), 2.61 (dt, J=5.3,11.1 Hz, 1H), 2.49 (dd, J=8.4, 12.7 Hz, 1H), 2.12 (dd, J=6.4, 17.1 Hz,1H), 2.08-2.01 (m, 1H), 1.99-1.91 (m, 1H), 1.88 (ddd, J=3.1, 3.3, 6.8Hz, 1H), 1.86-1.82 (m, 1H), 1.78 (d, J=11.0 Hz, 1H), 1.72 (br. s., 1H),1.71 (s, 3H), 1.69 (d, J=4.6 Hz, 1H), 1.67-1.63 (m, 1H), 1.61-1.53 (m,2H), 1.51 (br. s., 1H), 1.48 (br. s., 2H), 1.47-1.41 (m, 2H), 1.12 (dd,J=3.4, 13.4 Hz, 2H), 1.07 (s, 3H), 1.01 (br. s., 3H), 1.00 (s, 3H), 0.99(s, 3H), 0.97 (d, J=6.7 Hz, 3H), 0.93 (s, 3H), 0.93 (s, 3H).

Example 112 Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-3a-[[3-methyl-1-oxo-2-[(tetrahydro-1,1-dioxido-3-thienyl)amino]butyl]amino]-1H-cyclopenta[a]chrysen-9-yl]

The title compound was prepared in 30% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except2-(1,1-dioxo-tetrahydro-1lambda6-thiophene-3-yl-amino)-3-methylbutyricacid was used instead of 3-(dimethylamino)propionic acid hydrochloridein Step 1. LCMS: m/e 747.5 (M+H)⁺, 2.09 min (method 6). ¹H NMR (500 MHz,1:1 CDCl₃:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.25 (br. s., 1H), 7.19 (d,J=8.2 Hz, 2H), 5.28 (d, J=4.9 Hz, 1H), 4.78 (s, 1 H), 4.65 (br. s., 1H),3.73 (ddd, J=6.6, 6.7, 9.3 Hz, 1H), 3.47 (dd, J=7.2, 13.3 Hz, 1H), 3.41(dt, J=4.1, 8.6 Hz, 1H), 3.27 (br. s., 1H), 3.17-3.07 (m, 1H), 2.75-2.63(m, 2H), 2.59 (dd, J=7.2, 13.0 Hz, 1H), 2.43 (dd, J=8.5, 12.2 Hz, 1H),2.35 (dd, J=8.9, 12.8 Hz, 1H), 2.25-2.16 (m, 1H), 2.12 (dd, J=6.3, 17.2Hz, 1H), 1.91-1.76 (m, 3H), 1.74 (br. s., 1H), 1.71 (s, 3H), 1.69 (br.s., 1H), 1.58-1.47 (m, 6H), 1.46-1.35 (m, 4H), 1.35-1.28 (m, 1H), 1.25(d, J=9.8 Hz, 1H), 1.18-1.12 (m, 2H), 1.10 (d, J=6.7 Hz, 3H), 1.08 (s,3H), 1.06 (d, J=7.3 Hz, 3H), 1.03 (s, 3H), 1.00 (s, 3H), 0.93 (s, 3H),0.93 (br. s., 3H).

Example 113 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(1-(methylsulfonyl)pyrrolidine-2-carboxamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 17% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 1-(methylsulfonyl)pyrrolidine-2-carboxylic acid was usedinstead of 3-(dimethylamino)propionic acid hydrochloride in Step 1.LCMS: m/e 705.5 (M+H)⁺, 2.04 min (method 6). ¹H NMR (500 MHz, 1:1CDCl₃:MeOD) δ=7.92 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H), 6.88 (s,1H), 5.29 (dd, J=1.5, 6.1 Hz, 1H), 4.76 (d, J=1.5 Hz, 1H), 4.10 (dd,J=3.1, 8.8 Hz, 1H), 3.60 (ddd, J=3.5, 7.0, 10.2 Hz, 1H), 3.40 (dt,J=6.4, 9.6 Hz, 1H), 2.96 (s, 3H), 2.62-2.52 (m, 2H), 2.42 (dd, J=8.2,11.6 Hz, 1H), 2.31 (dddd, J=3.2, 3.4, 6.4, 9.7 Hz, 1H), 2.21-2.16 (m,1H), 2.16-2.10 (m, 1H), 2.03 (tdd, J=3.2, 6.6, 13.0 Hz, 1H), 1.99-1.89(m, 2H), 1.82-1.75 (m, 1H), 1.75-1.72 (m, 1H), 1.70 (s, 3H), 1.69-1.66(m, 1H), 1.58-1.46 (m, 6H), 1.46-1.29 (m, 5H), 1.28-1.22 (m, 1H), 1.14(d, J=13.1 Hz, 2H), 1.09 (s, 3H), 1.03 (s, 3H), 1.01 (s, 3H), 0.93 (s,6H).

Example 114 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 29% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except(S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acidwas used instead of 3-(dimethylamino)propionic acid hydrochloride inStep 1. LCMS: m/e 763.5 (M+H)⁺, 2.55 min (method 6). ¹H NMR (500 MHz,1:1 CDCl₃:MeOD) δ=7.92 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 6.46(br. s., 1H), 5.29 (dd, J=1.7, 6.3 Hz, 1H), 4.72 (s, 1H), 4.63 (br. s.,1H), 4.50 (d, J=9.2 Hz, 1H), 3.84 (br. s., 1H), 3.72 (td, J=6.7, 13.4Hz, 1H), 2.84 (br. s., 1H), 2.55 (d, J=13.4 Hz, 1H), 2.51-2.37 (m, 2H),2.12 (dd, J=6.4, 17.1 Hz, 1H), 1.96 (br. s., 1H), 1.73 (br. s., 1H),1.70 (s, 4H), 1.61 (br. s., 2H), 1.56 (br. s., 9H), 1.53-1.45 (m, 5H),1.45-1.37 (m, 3H), 1.36-1.29 (m, 2H), 1.28-1.23 (m, 1H), 1.17-1.09 (m,2H), 1.08 (s, 3H), 1.02 (s, 6H), 0.94 (s, 3H), 0.93 (s, 3H).

Example 115 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(thiophene-2-sulfonamido)acetamido)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 31% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-(thiophene-2-sulfonamido)acetic acid was used instead of3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 733.6(M+H)⁺, 2.06 min (method 6). ¹H NMR (500 MHz, 1:1 CDCl₃:MeOD) δ=7.92 (d,J=8.5 Hz, 2H), 7.73 (dd, J=1.4, 5.0 Hz, 1H), 7.66 (dd, J=1.2, 3.7 Hz,1H), 7.20 (d, J=8.2 Hz, 2H), 7.16 (dd, J=3.8, 5.0 Hz, 1H), 6.88 (s, 1H),5.32-5.26 (m, 1H), 4.78 (d, J=1.5 Hz, 1H), 3.58-3.45 (m, 2H), 2.63-2.57(m, 1H), 2.56-2.50 (m, 1H), 2.42 (dd, J=8.2, 12.2 Hz, 1H), 2.13 (dd,J=6.3, 17.2 Hz, 1H), 1.98-1.88 (m, 1H), 1.87-1.76 (m, 2H), 1.73 (br. s.,1H), 1.72 (s, 3H), 1.70-1.66 (m, 1H), 1.63-1.53 (m, 3H), 1.53-1.46 (m,4H), 1.45-1.37 (m, 3H), 1.37-1.30 (m, 2H), 1.28-1.22 (m, 1H), 1.14 (s,3H), 1.10 (d, J=3.1 Hz, 1H), 1.03 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H),0.94 (br. s., 3H).

Example 116 Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-3a-[[1-oxo-2-[(tetrahydro-1,1-dioxido-3-thienyl)amino]butyl]amino]-1H-cyclopenta[a]chrysen-9-yl]

The title compound was prepared in 19% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except2-(1,1-dioxo-tetrahydro-1lambda6-thiophene-3-yl-amino)-butyric acid wasused instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1.LCMS: m/e 733.6 (M+H)⁺, 2.00 min (method 6). 1H NMR (500 MHz, 1:1CDCl₃:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.38 (br. s., 1H), 7.20 (d, J=8.2Hz, 2H), 5.29 (d, J=4.6 Hz, 1H), 4.77 (d, J=8.5 Hz, 1H), 3.77 (br. s.,1H), 3.51-3.36 (m, 2H), 3.22-3.09 (m, 2H), 2.65 (d, J=15.9 Hz, 3H), 2.37(br. s., 2H), 2.13 (dd, J=6.4, 17.4 Hz, 1H), 1.96-1.77 (m, 5H), 1.73(br. s., 1H), 1.73 (s, 3H), 1.72-1.67 (m, 1H), 1.61-1.52 (m, 2H), 1.50(d, J=2.1 Hz, 3H), 1.48-1.30 (m, 6H), 1.29-1.23 (m, 1H), 1.22-1.14 (m,2H), 1.12 (s, 2H), 1.09 (d, J=1.8 Hz, 2H), 1.08-1.05 (m, 1H), 1.04 (d,J=1.8 Hz, 4H), 1.03 (d, J=4.0 Hz, 4H), 0.95 (br. s., 3H), 0.94 (br. s.,3H).

Example 117 Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-3a-[[(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)acetyl]amino]-1H-cyclopenta[a]chrysen-9-yl]

The title compound was prepared in 13% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except (1,1-dioxo-1,6-[1,2]thiazinan-2-yl)acetic acid was usedinstead of 3-(dimethylamino)propionic acid hydrochloride in Step 1.LCMS: m/e 705.5 (M+H)⁺, 2.01 min (method 6). ¹H NMR (500 MHz,METHANOL-d₄) δ=7.92 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 6.83 (s,1H), 5.32-5.26 (m, 1H), 4.77 (d, J=1.5 Hz, 1H), 4.64 (s, 1H), 3.83-3.72(m, 2H), 3.63-3.46 (m, 2H), 3.37 (s, 2H), 3.21-3.11 (m, 2H), 2.62-2.54(m, 1H), 2.53-2.50 (m, 1H), 2.49-2.41 (m, 1H), 2.32-2.23 (m, 2H), 2.13(dd, J=6.6, 17.2 Hz, 1H), 1.99-1.87 (m, 1H), 1.78 (br. s., 1H),1.77-1.73 (m, 3H), 1.72 (s, 3H), 1.71-1.67 (m, 1H), 1.62-1.51 (m, 3H),1.48 (d, J=5.2 Hz, 3H), 1.46-1.31 (m, 5H), 1.28-1.23 (m, 1H), 1.14 (d,J=13.4 Hz, 2H), 1.11 (s, 3H), 1.03 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H),0.94 (s, 3H).

Example 118 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(4,4-difluoropiperidin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-bromoacetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,HCl (403 mg, 0.694 mmol) in DCM (10 mL) was addedN,N-diisopropylethylamine (0.484 mL, 2.78 mmol), bromoacetic acid (106mg, 0.764 mmol) and2-(3H-[1,2,3]triazolo[4,5-β]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (317 mg, 0.833 mmol). The reaction mixture wasstirred at rt for 15 h. Then, the reaction was concentrated and thecrude residue was dissolved in THF (3.0 mL) filtered and purified byreverse phase preparative HPLC using HPLC method 3 to give methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-bromoacetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(148.9 mg, 0.224 mmol, 32.3% yield) as white solid. LCMS: m/e 664.6(M+H)⁺, 2.41 min (method 6).

Step 2. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(4,4-difluoropiperidin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-bromoacetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(30 mg, 0.045 mmol) in THF (3 mL) was added N,N-diisopropylethylamine(0.039 mL, 0.226 mmol) and 4,4-difluoropiperidine, HCl (21.34 mg, 0.135mmol). The reaction mixture was stirred at 80° C. for 18 h. AdditionalN,N-diisopropylethylamine (0.078 mL, 0.452 mmol) and4,4-difluoropiperidine, HCl (40 mg, 0.354 mmol) were added, and themixture was heated to 150° C. in a microwave for 7.5 h. The mixture wasconcentrated to brown viscous oil. The crude residue was dissolved inTHF (1.5 mL), filtered and purified by reverse phase preparative HPLCusing HPLC method 3 to give methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(4,4-difluoropiperidin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,TFA (13.1 mg, 0.016 mmol, 35.4% yield) as white solid. LCMS: m/e 705.6(M+H)⁺, 2.95 min (method 6). ¹H NMR (500 MHz, CHLOROFORM-d) δ=7.94 (d,J=8.5 Hz, 2H), 7.90-7.80 (m, 1H), 7.21 (d, J=8.2 Hz, 2H), 6.32 (s, 1H),5.31 (dd, J=1.4, 6.0 Hz, 1H), 4.77 (s, 1H), 4.67 (s, 1H), 3.93 (s, 3H),3.72-3.61 (m, 3H), 3.51-3.41 (m, 5H), 2.83 (d, J=2.7 Hz, 2H), 2.63 (d,J=13.1 Hz, 1H), 2.56 (dt, J=5.3, 10.9 Hz, 1H), 2.39 (dd, J=8.2, 12.8 Hz,1H), 2.12 (dd, J=6.4, 17.1 Hz, 1H), 1.91-1.81 (m, 1H), 1.79-1.73 (m,2H), 1.72 (s, 3H), 1.70-1.64 (m, 1H), 1.54-1.40 (m, 7H), 1.39-1.26 (m,3H), 1.26-1.21 (m, 1H), 1.18-1.09 (m, 2H), 1.04 (s, 3H), 1.02 (s, 3H),1.00 (s, 3H), 0.95 (br. s., 3H), 0.94 (br. s., 3H).

Step 3. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(4,4-difluoropiperidin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(4,4-difluoropiperidin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(13.1 mg, 0.019 mmol) in THF (3 mL) was added a 0.753 molar aqueoussolution of LiOH.H₂O (0.149 mL, 0.074 mmol). The reaction was heated to75° C. for 6 h. The reaction was concentrated to brown viscous oil, andthe crude material was purified by reverse phase preparative HPLC usingHPLC method 3 to give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(4,4-difluoropiperidin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA (9.4 mg, 0.012 mmol, 62.8% yield) as white solid. LCMS: m/e691.6 (M+H)⁺, 2.34 min (method 6). ¹H NMR (500 MHz, METHANOL-d₄) δ=7.92(d, J=8.2 Hz, 2H), 7.43 (s, 1H), 7.20 (d, J=8.5 Hz, 2H), 5.30 (dd,J=1.7, 6.3 Hz, 1H), 4.75 (d, J=1.2 Hz, 1H), 4.66 (d, J=1.5 Hz, 1H),3.71-3.58 (m, 2H), 3.24 (br. s., 3H), 2.67-2.61 (m, 1H), 2.57 (dt,J=5.3, 11.1 Hz, 1H), 2.41 (dd, J=8.2, 12.5 Hz, 1H), 2.33-2.22 (m, 4H),2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.95-1.83 (m, 1H), 1.81 (d, J=9.2 Hz,2H), 1.74 (br. s., 1H), 1.72 (s, 3H), 1.71-1.67 (m, 1H), 1.59-1.43 (m,8H), 1.42-1.31 (m, 3H), 1.29-1.23 (m, 1H), 1.18-1.12 (m, 2H), 1.09 (s,3H), 1.04 (s, 3H), 1.02 (s, 3H), 0.95 (s, 3H), 0.94 (br. s., 3H).

Example 119 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(3,3-difluoropyrrolidin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 38% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(4,4-difluoropiperidin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except and 3,3-difluoropyrrolidine, HCl was used instead of4,4-difluoropiperidine, HCl in Step 2. LCMS: m/e 677.5 (M+H)⁺, 2.26 min(method 6). ¹H NMR (500 MHz, 1:1 CDCl₃:MeOD) δ=7.92 (d, J=8.2 Hz, 2H),7.40 (s, 1H), 7.20 (d, J=8.2 Hz, 2H), 5.29 (dd, J=1.7, 6.3 Hz, 1H), 4.75(d, J=1.2 Hz, 1H), 4.65 (s, 1H), 3.59-3.44 (m, 2H), 3.43-3.36 (m, 1H),3.31-3.20 (m, 2H), 2.63-2.55 (m, 1H), 2.55-2.47 (m, 3H), 2.47-2.39 (m,1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.94-1.83 (m, 1H), 1.81-1.76 (m,2H), 1.76-1.73 (m, 1H), 1.72 (s, 3H), 1.70-1.65 (m, 1H), 1.57-1.46 (m,6H), 1.46-1.40 (m, 2H), 1.39-1.31 (m, 2H), 1.26 (dd, J=2.7, 10.7 Hz,1H), 1.19-1.10 (m, 2H), 1.09 (s, 3H), 1.03 (s, 3H), 1.02 (s, 3H), 0.95(s, 3H), 0.94 (s, 3H).

General Procedure for Parallel Synthesis of C-17 Amides:

A stock solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,HCl (0.990 g, 1.7 mmol) and DIPEA (1.10 g, 8.52 mmol) in DCE (13 mL) wasprepared. A stock solution of the HATU (1.94 g, 5.11 mmol) in DCE (13mL) was prepared. To each of the carboxylic acids (0.393 mmol) weighedinto 16×100 mm Wheaton vials was added 1 mL of the stock HATU solution.The vials were capped and shaken at rt for 10 min before adding 1 mL ofthe stock methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,HCl/DIPEA solution to each vial. The vials were capped and shaken at rtfor 18 h. Samples were concentrated. A stock solution of lithiumhydroxide monohydrate (0.286 g, 6.81 mmol) in water (6.50 mL) wasprepared. To each of the reaction vials was added 2.5 mL of THF and 0.5mL of the stock lithium hydroxide solution. The vials were capped andthe reactions were stirred at 75° C. for 18 h. Added an additional 0.5mL of the stock lithium hydroxide solution and stirred at 75° C. for anadditional 48 h. Samples were concentrated, redissolved in a smallquantity of a mixture of THF and methanol, filtered and purified byreverse phase preparative HPLC.

Example 120 Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-3a-[(3-pyridinylacetyl)amino]-1H-cyclopenta[a]chrysen-9-yl]

The title compound was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure described for the parallel synthesis ofC-17 amides above, using pyridylacetic acid hydrochloride as thereacting carboxylic acid. LCMS: m/e 649.6 (M+H)⁺, 4.09 min (method 3).

Example 121 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridin-3-yloxy)acetamido)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure described for the parallel synthesis ofC-17 amides above, using 3-pyridyloxyacetic acid as the reactingcarboxylic acid. LCMS: m/e 665.6 (M+H)⁺, 4.37 min (method 3).

Example 122 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(piperidin-1-yl)acetamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure described for the parallel synthesis ofC-17 amides above, using piperidin-1-ylacetic acid hydrochloride as thereacting carboxylic acid. LCMS: m/e 655.7 (M+H)⁺, 4.68 min (method 3).

Example 123 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(diisopropylamino)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure described for the parallel synthesis ofC-17 amides above, using diisopropylamino-acetic acid as the reactingcarboxylic acid. LCMS: m/e 671.7 (M+H)⁺, 4.99 min (method 3). ¹H NMR(599 MHz, <DMSO_CDCl₃>) δ=8.45-8.37 (m, 1H), 7.89 (d, J=8.2 Hz, 2H),7.69-7.65 (m, 1H), 7.24-7.20 (m, 2H), 5.31-5.24 (m, 1H), 4.79-4.73 (m,1H), 4.67-4.62 (m, 1H), 3.95 (br. s., 2H), 3.66 (d, J=5.9 Hz, 3H), 2.94(s, 1H), 2.78 (s, 1H), 2.74 (br. s., 1H), 2.63 (d, J=13.5 Hz, 1H), 2.30(t, J=9.1 Hz, 1H), 2.13 (dd, J=6.2, 16.7 Hz, 1H), 2.07-1.98 (m, 1H),1.75 (br. s., 1H), 1.72 (s, 4H), 1.69-1.61 (m, 1H), 1.52-1.41 (m, 8H),1.36-1.33 (m, 3H), 1.33-1.31 (m, 2H), 1.30-1.28 (m, 3H), 1.28-1.25 (m,3H), 1.09 (s, 6H), 1.01 (s, 6H), 0.93 (br. s., 6H).

Example 124 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(2-methylpiperidin-1-yl)acetamido)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure described for the parallel synthesis ofC-17 amides above, using (2-methylpiperidin-1-yl)acetic acid as thereacting carboxylic acid. LCMS: m/e 669.7 (M+H)⁺, 4.73 min (method 3).

Example 125 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(4-fluorophenylamino)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure described for the parallel synthesis ofC-17 amides above, using (4-fluorophenylamino)acetic acid as thereacting carboxylic acid. LCMS: m/e 681.7 (M+H)⁺, 6.62 min (method 3).

Example 126 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyrimidin-2-yl)acetamido)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure described for the parallel synthesis ofC-17 amides above, using 2-pyrimidine acetic acid as the reactingcarboxylic acid. LCMS: m/e 650.6 (M+H)⁺, 5.57 min (method 3). ¹H NMR(599 MHz, <DMSO_CDCl₃>) δ=8.78 (d, J=4.7 Hz, 2H), 7.88 (d, J=8.2 Hz,2H), 7.29 (s, 1H), 7.22 (d, J=7.6 Hz, 2H), 5.28 (d, J=5.3

Hz, 1H), 4.75 (s, 1H), 4.62 (br. s., 1H), 3.93 (s, 1H), 3.82 (d, J=14.6Hz, 1H), 2.77-2.72 (m, 1H), 2.63 (d, J=12.9 Hz, 1H), 2.40-2.32 (m, 1H),2.16-2.04 (m, 1H), 2.00-1.81 (m, 2H), 1.73 (br. s., 2H), 1.71 (s, 3H),1.67-1.52 (m, 4H), 1.50-1.39 (m, 7H), 1.36-1.20 (m, 7H), 0.99 (br. s.,6H), 0.98 (br. s., 3H), 0.93 (br. s., 3H), 0.93 (br. s., 3H).

Example 127 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridin-2-yl)acetamido)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure described for the parallel synthesis ofC-17 amides above, using 2-pyridylacetic acid hydrochloride as thereacting carboxylic acid. LCMS: m/e 649.6 (M+H)⁺, 4.23 min (method 3).

Example 128 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridin-3-yl)acetamido)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure described for the parallel synthesis ofC-17 amides above, using 3-pyridylacetic acid hydrochloride as thereacting carboxylic acid. LCMS: m/e 649.6 (M+H)⁺, 4.07 min (method 3).¹H NMR (599 MHz, <DMSO_CDCl₃>) δ=8.49 (d, J=5.3 Hz, 2H), 7.88 (s, 2H),7.33 (d, J=5.3 Hz, 2H), 7.22 (d, J=8.2 Hz, 2H), 7.17 (s, 1H), 5.28 (d,J=5.3 Hz, 1H), 4.86-4.81 (m, 1H), 4.76 (s, 1H), 4.63 (br. s., 1H), 3.66(d, J=12.9 Hz, 1H), 3.49 (d, J=12.9 Hz, 1H), 2.85-2.79 (m, 1H),2.60-2.56 (m, 1H), 2.35-2.28 (m, 1H), 2.12 (dd, J=6.4, 17.0 Hz, 1H),2.06 (t, J=11.1 Hz, 1H), 1.87-1.79 (m, 1H), 1.73 (br. s., 2H), 1.71 (s,3H), 1.61-1.50 (m, 2H), 1.50-1.35 (m, 6H), 1.37-1.27 (m, 3H), 1.24 (d,J=9.4 Hz, 3H), 1.13-1.05 (m, J=12.9 Hz, 1H), 1.03-1.00 (m, 6H), 0.97 (s,3H), 0.94 (s, 3H), 0.93 (s, 3H).

Example 129 Preparation of4-((1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((1,1-dioxido-4-thiomorpholinyl)acetyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-[(1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxo-1,4-thiazinan-4-yl)acetyl]amino]-1-isopropyl-5a,5b,8,8,11a-pentamethyl-1,2,3,4,5,6,7,7a,11,11b,12,13,13a,13b-tetradecahydrocyclopenta[a]chrysen-9-yl]benzoate

A solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(152 mg, 0.211 mmol) in THF (10 mL) was flushed with N₂(g) and palladiumhydroxide (44.5 mg, 0.063 mmol) was added. The reaction mixture waspurged with H₂ (g) then stirred under H₂ (g) atmosphere. After 68 h, thereaction was purged with N₂ (g), the catalyst was removed by filteringthrough celite and washed with DCM. The resulting liquid filtrate wasconcentrated to a viscous oil which was dissolved in THF (2.0 mL)filtered and injected into reverse phase HPLC for purification usingHPLC method 5 to give the title compound (28.8 mg, 0.040 mmol, 18.89%yield; 62.8% yield based on recovered starting material). LCMS: m/z721.6 (M+H⁺), retention time 2.655 min (method 6). ¹H NMR (500 MHz,CHLOROFORM-d) δ=8.47 (br. s., 2H), 7.95 (d, J=8.2 Hz, 2H), 7.22 (d,J=8.5 Hz, 2H), 6.98 (s, 1H), 5.32 (dd, J=1.5, 6.1 Hz, 1H), 3.94 (s, 3H),3.69-3.61 (m, 1H), 3.58-3.52 (m, 4H), 3.31-3.27 (m, 3H), 2.65 (d, J=11.6Hz, 1H), 2.37 (dd, J=7.5, 12.7 Hz, 1H), 2.20-2.11 (m, 1H), 1.98-1.86 (m,1H), 1.72 (d, J=15.9 Hz, 3H), 1.62-1.52 (m, 3H), 1.52-1.36 (m, 9H),1.34-1.23 (m, 3H), 1.21-1.14 (m, 2H), 1.03 (s, 3H), 1.02 (br. s., 3H),1.01 (br. s., 3H), 0.95 (s, 6H), 0.91 (d, J=7.0 Hz, 3H), 0.81 (d, J=6.7Hz, 3H).

Step 2. Preparation of4-((1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((1,1-dioxido-4-thiomorpholinyl)acetyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a solution of methyl4-[(1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxo-1,4-thiazinan-4-yl)acetyl]amino]-1-isopropyl-5a,5b,8,8,11a-pentamethyl-1,2,3,4,5,6,7,7a,11,11b,12,13,13a,13b-tetradecahydrocyclopenta[a]chrysen-9-yl]benzoate,TFA (33 mg, 0.040 mmol) in THF (Volume: 3 mL) was added a 0.753 molarsolution of lithium hydroxide monohydrate (0.316 mL, 0.158 mmol) in H₂O.The reaction mixture was heated to 75° C. After 5.5 h, the reaction wasconcentrated to dryness. The crude residue was dissolved in THF (1.2mL), MeOH (0.3 mL) and 1N HCl (0.2 mL). The solution was filtered andinjected into reverse phase HPLC for purification using HPLC method 3 togive4-((1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((1,1-dioxido-4-thiomorpholinyl)acetyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA (17.9 mg, 0.021 mmol, 54.1% yield) as a white solid. LCMS: m/z707.6 (M+H⁺), retention time 2.030 min (method 6). ¹H NMR (500 MHz,METHANOL-d₄) δ=7.93 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 7.13 (s,1H), 5.31 (dd, J=1.5, 6.1 Hz, 1H), 3.26-3.22 (m, 5H), 3.21-3.15 (m, 4H),2.66-2.59 (m, 1H), 2.37 (dd, J=6.7, 12.5 Hz, 1H), 2.17 (dd, J=6.4, 17.1Hz, 1H), 1.99-1.91 (m, 1H), 1.80-1.70 (m, 4H), 1.67-1.57 (m, 2H),1.57-1.45 (m, 9H), 1.44-1.39 (m, 1H), 1.39-1.26 (m, 3H), 1.18-1.11 (m,2H), 1.09 (s, 3H), 1.04 (s, 6H), 0.96 (s, 3H), 0.95 (s, 3H), 0.91 (d,J=7.0 Hz, 3H), 0.82 (d, J=6.7 Hz, 3H).

Example 130 Preparation of4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-(((1,1-dioxido-4-thiomorpholinyl)acetyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-[(1S,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxo-1,4-thiazinan-4-yl)acetyl]amino]-1-isopropyl-5a,5b,8,8,11a-pentamethyl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysen-9-yl]benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(51 mg, 0.071 mmol) in THF (3 mL) was added palladium on activatedcharcoal (10% Pd content) (18 mg, 0.017 mmol). The reaction mixture waspurged by bubbling H₂ (g) slowly into the mixture over 30 mins. and thenthe mixture was stirred under H₂ (g) atmosphere. After 24 h, thereaction mixture was purged with N₂ (g) and more catalyst (36 mg, 0.034mmol) was added. The reaction mixture was stirred under H₂ (g) for anadditional 24 h. The mixture was then purged with N₂ (g), and thecatalyst was filtered and washed with THF. The liquid filtrate wasconcentrated. The crude residue was purified by preparative HPLC usingHPLC method 5 to give methyl4-[(1S,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxo-1,4-thiazinan-4-yl)acetyl]amino]-1-isopropyl-5a,5b,8,8,11a-pentamethyl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysen-9-yl]benzoate,TFA (24.4 mg, 0.029 mmol, 41.1% yield) as a white solid. LCMS: m/z 723.6(M+H⁺), retention time 2.648 min (method 6). ¹H NMR (500 MHz,CHLOROFORM-d) δ=7.94 (d, J=8.2 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 7.13(br. s., 2H), 7.05 (s, 1H), 3.56-3.49 (m, 1H), 3.48-3.39 (m, 5H),3.27-3.19 (m, 4H), 2.66 (d, J=12.5 Hz, 1H), 2.42 (dd, J=3.2, 13.3 Hz,1H), 2.40-2.34 (m, 1H), 2.16-2.07 (m, 1H), 1.96-1.90 (m, 1H), 1.74-1.60(m, 6H), 1.59-1.51 (m, 2H), 1.51-1.38 (m, 9H), 1.37-1.31 (m, 2H),1.30-1.26 (m, 1H), 1.21-1.10 (m, 2H), 1.03 (s, 3H), 1.01 (s, 3H), 0.98(s, 3H), 0.95 (s, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.81 (d, J=6.7 Hz, 3H),0.78 (s, 3H), 0.72 (s, 3H). ¹³C NMR (CHLOROFORM-d) δ ppm 167.7, 167.2,149.5, 129.8, 129.4, 128.4, 128.3, 127.5, 65.9, 58.8, 57.3, 55.7, 51.8,51.3, 49.9, 49.9, 48.2, 44.7, 41.9, 40.4, 40.3, 37.9, 37.4, 37.3, 34.5,34.0, 29.4, 29.2, 28.1, 26.8, 26.2, 24.6, 22.6, 21.8, 20.4, 18.5, 17.4,16.1, 15.6, 14.5, 14.1.

Step 2. Preparation4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-(((1,1-dioxido-4-thiomorpholinyl)acetyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a solution of4-[(1S,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxo-1,4-thiazinan-4-yl)acetyl]amino]-1-isopropyl-5a,5b,8,8,11a-pentamethyl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysen-9-yl]benzoate,TFA (24.3 mg, 0.029 mmol) in THF (3 mL) was added a 0.753 molar aqueoussolution of lithium hydroxide monohydrate (0.232 mL, 0.116 mmol). Thereaction mixture was heated to 75° C. After 5.5 h, the reaction mixturewas concentrated to dryness. The crude residue was dissolved in THF (1.2mL), MeOH (0.3 mL) and 1N HCl (0.2 mL). The resulting solution wasfiltered and purified using prep HPLC method 3 to give4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-(((1,1-dioxido-4-thiomorpholinyl)acetyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA (16.5 mg, 0.020 mmol, 69.1% yield) as a white solid. LCMS: m/z709.6 (M+H⁺), retention time 2.072 min (method 6). ¹H NMR (500 MHz,METHANOL-d₄) δ=7.91 (d, J=8.2 Hz, 2H), 7.26 (d, J=8.2 Hz, 2H), 7.11 (s,1H), 3.25-3.20 (m, 6H), 3.17 (d, J=5.5 Hz, 4H), 2.65-2.59 (m, 1H), 2.44(dd, J=2.7, 13.1 Hz, 1H), 2.37 (dd, J=7.0, 12.5 Hz, 1H), 2.19-2.04 (m,1H), 1.98-1.89 (m, 1H), 1.85 (d, J=13.1 Hz, 1H), 1.74 (dd, J=3.7, 7.9Hz, 2H), 1.71-1.60 (m, 3H), 1.56-1.45 (m, 8H), 1.44-1.37 (m, 4H),1.36-1.25 (m, 2H), 1.16-1.09 (m, 2H), 1.05 (s, 3H), 1.04 (s, 3H), 1.00(s, 3H), 0.95 (d, J=2.1 Hz, 1H), 0.91 (d, J=6.7 Hz, 3H), 0.81 (d, J=6.7Hz, 3H), 0.78 (s, 3H), 0.72 (s, 3H).

Example 130-1 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(carboxyformamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compounds was obtained in 25% yield as a by-product during theester hydrolysis in Step 2 of the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoacetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid. LCMS: m/e 600.5 (M−H)⁻, 1.33 min (method 5). ¹H NMR (500 MHz,CHLOROFORM-d) δ=8.02 (d, J=8.2 Hz, 2H), 7.26 (d, J=8.2 Hz, 3H), 5.33 (d,J=4.9 Hz, 1H), 4.80 (s, 1H), 4.70 (s, 1H), 3.84-3.80 (m, 1H), 2.59 (d,J=10.1 Hz, 1H), 2.54 (d, J=5.2 Hz, 1H), 2.46 (dd, J=8.4, 11.7 Hz, 1H),2.18-2.11 (m, 1H), 1.91 (ddd, J=3.1, 3.3, 6.8 Hz, 2H), 1.83-1.75 (m,2H), 1.74 (s, 3H), 1.62-1.34 (m, 12H), 1.28 (s, 1H), 1.27-1.12 (m, 3H),1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.97 (br. s., 3H), 0.96 (br.s., 3H).

Example 130-2 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(1-(tert-butoxycarbonylamino)cyclopropanecarboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(1-(tert-butoxycarbonylamino)cyclopropanecarboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.302 g, 0.555 mmol) and N,N-diisopropylethylamine (0.580 mL, 3.33mmol) in DCM (5 mL) was added2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (0.465 g, 1.222 mmol) and1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid (0.223 g, 1.111mmol). The reaction mixture was stirred at rt. After 18 h, the reactionwas diluted with DCM (20 mL) and silica gel (4 g) was added. The mixturewas concentrated to dryness and dried in vacuo to a free flowing powder.The material was loaded onto a silica gel column (25 g cartridge)gradient 100% hexanes to 25% EtOAc in hexanes over 240 mL, hold 25%EtOAc in hexanes to give methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(1-(tert-butoxycarbonylamino)cyclopropanecarboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(234 mg, 0.309 mmol, 55.6% yield) as a white solid. LCMS: m/e 727.4(M+H)⁺, 5.17 min (method 2). ¹H NMR (500 MHz, CHLOROFORM-d) δ 7.97-7.89(m, 2H), 7.20 (d, J=8.5 Hz, 2H), 6.47 (br. s., 1H), 5.30 (dd, J=6.3, 1.7Hz, 1H), 5.16-5.06 (m, 1H), 4.72 (d, J=1.8 Hz, 1H), 4.62 (s, 1H),4.19-4.09 (m, 1H), 3.92 (s, 3H), 2.66-2.60 (m, 1H), 2.49 (d, J=4.6 Hz,2H), 2.11 (dd, J=17.1, 6.4 Hz, 1H), 2.07-1.96 (m, 1H), 1.53 (s, 9H),1.46 (s, 3H), 1.43 (d, J=2.7 Hz, 1H), 1.37 (d, J=3.4 Hz, 1H), 1.34 (d,J=3.7 Hz, 1H), 1.26 (dd, J=7.0, 3.1 Hz, 1H), 1.19-1.16 (m, 1H), 1.12(br. s., 3H), 1.10-1.07 (m, 1H), 1.01 (s, 3H), 1.01-0.99 (m, 3H), 0.94(s, 3H), 0.94 (s, 3H).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(1-(tert-butoxycarbonylamino)cyclopropanecarboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(1-(tert-butoxycarbonylamino)cyclopropanecarboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(101 mg, 0.139 mmol) in THF (5 mL) was added a solution of lithiumhydroxide monohydrate (17.49 mg, 0.417 mmol) in water (1.000 mL). Theresulting mixture was stirred at 75° C. After 18 h, the reaction mixturewas concentrated. The residue was redissolved in THF/MeOH, silica gel (2g) was added and the mixture was concentrated to dryness. The absorbedmaterial was loaded onto a silica gel column (25 g cartridge) and elutedwith 0% B (solvent B=(90:10 DCM:MeOH, A=100% DCM) to 50% B for 180 mL,then hold at 50% B for 900 mL. Thus was obtained4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(1-(tert-butoxycarbonylamino)cyclopropanecarboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (39 mg, 0.054 mmol, 38.6% yield) as white solid. LCMS: m/e 713.6(M+H)⁺, 2.32 min (method 1). ¹H NMR (500 MHz, 1:1 CDCl₃:METHANOL-d₄) δ7.92 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 3H), 6.62 (br. s., 1H),5.33-5.24 (m, 1H), 4.72 (s, 1H), 4.63 (s, 1H), 2.61-2.36 (m, 3H), 2.13(dd, J=17.2, 6.3 Hz, 1H), 2.04-1.95 (m, 1H), 1.73 (br. s., 1H), 1.71 (s,3H), 1.41 (d, J=6.1 Hz, 2H), 1.26 (br. s., 9H), 1.15 (s, 3H), 1.10 (br.s., 1H), 1.03 (s, 3H), 1.02 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H), 0.88(d, J=6.7 Hz, 2H), 0.86-0.83 (m, 2H).

Example 130-3 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(1-(tert-butoxycarbonylamino)cyclopropanecarboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1R,3S)-3-(((benzyloxy)carbonyl)amino)-2,2-dimethylcyclobutanecarboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,HCl (265 mg, 0.457 mmol) in tetrahydrofuran (5 mL) was addedN,N-di-iso-propylethylamine (0.278 mL, 1.598 mmol),(1R,3S)-3-(((benzyloxy)carbonyl)amino)-2,2-dimethylcyclobutanecarboxylicacid (152 mg, 0.548 mmol) (for preparation see: J. Aguilera et al.Tetrahedron Asymmetry 2008, 19, 302) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (226 mg, 0.594 mmol). The reaction mixture washeated to 50° C. After 6 h, the mixture was dilute with EtOAc (30 mL)and washed with 1N HCl (5 mL). The aqueous layer was extracted withEtOAc (25 mL). The combined organic layer was washed with 5% NaHCO₃,brine, dried over MgSO₄, filtered and concentrated to afford a lightbrown viscous oil. The material was dissolved in DCM, loaded onto asilicagel column and eluted with 97:3 DCM:MeOH to give methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1R,3S)-3-(((benzyloxy)carbonyl)amino)-2,2-dimethylcyclobutanecarboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(335 mg, 0.355 mmol, 78% yield) as brown foam. LC/MS: m/e 802.4 (M+H)⁺,4.23 min (method 8). ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.95 (d, J=8.3 Hz,2H), 7.40-7.37 (m, 5H), 7.21 (d, J=8.3 Hz, 2H), 5.31 (d, J=4.6 Hz, 1H),5.18-5.12 (m, 2H), 5.10-5.06 (m, 1H), 4.97 (s, 1H), 4.76 (s, 1H), 4.66(s, 1H), 3.93 (s, 3H), 2.85 (s, 6H), 2.69-2.55 (m, 2H), 2.44-2.29 (m,3H), 2.17-2.09 (m, 2H), 1.94-1.81 (m, 3H), 1.72 (s, 3H), 1.70-1.66 (m,1H), 1.62-1.52 (m, 4H), 1.46 (d, J=7.3 Hz, 1H), 1.42 (d, J=2.7 Hz, 1H),1.37 (s, 3H), 1.32-1.22 (m, 3H), 1.15 (d, J=11.7 Hz, 2H), 1.09 (s, 2H),1.02 (s, 3H), 1.01 (s, 3H), 1.00 (s, 3H), 0.95 (s, 6H).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1R,3S)-3-(((benzyloxy)carbonyl)amino)-2,2-dimethylcyclobutanecarboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1R,3S)-3-(((benzyloxy)carbonyl)amino)-2,2-dimethylcyclobutanecarboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(135 mg, 0.168 mmol) in THF (5 mL), MeOH (2 mL) was added a solution oflithium hydroxide monohydrate (0.014 mL, 0.504 mmol) in water (1 mL).The reaction mixture was stirred at 75° C. After 4 h, the mixture wasconcentrated to a white paste. The crude material was dissolved in THF(1.75 mL), MeOH (1 mL) and 1N HCl (0.25 mL) and injected into a reversephase prep-HPLC using HPLC method 11 and dried in a vacuum oven to givethe title compound (30.4 mg, 0.035 mmol, 21.09% yield) as white solid.LCMS: m/e 789.4 (M+H)⁺, 3.14 min (method 8). ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.02 (d, J=8.3 Hz, 2H), 7.41-7.37 (m, 4H), 7.36 (d,J=3.4 Hz, 1H), 7.25 (d, J=8.3 Hz, 2H), 5.33 (d, J=4.6 Hz, 1H), 5.19-5.07(m, 3H), 4.99 (br. s., 1H), 4.77 (s, 1H), 4.66 (s, 1H), 3.98-3.88 (m,1H), 2.70-2.55 (m, 3H), 2.47-2.28 (m, 3H), 2.19-2.09 (m, 2H), 1.99-1.87(m, 1H), 1.76 (d, J=7.8 Hz, 1H), 1.72 (s, 3H), 1.71-1.63 (m, 2H), 1.58(d, J=8.1 Hz, 3H), 1.50 (br. s., 3H), 1.43 (br. s., 1H), 1.37 (br. s.,3H), 1.33 (d, J=12.2 Hz, 2H), 1.28 (s, 3H), 1.24 (d, J=7.1 Hz, 1H), 1.16(d, J=12.2 Hz, 2H), 1.09 (s, 3H), 1.02 (s, 6H), 1.01 (br. s., 3H), 0.96(s, 6H).

Section 4. Sulfonyl Amides Example 131 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(pyridin-2-ylmethylsulfonamido)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1: Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(pyridin-2-ylmethylsulfonamido)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

Methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.100 g, 0.184 mmol) was combined with pyridin-2-ylmethanesulfonylchloride, triflic acid salt (0.189 g, 0.552 mmol). To the mixture wasadded dry 1,4-dioxane (1.5 mL) followed by addition of DIPEA (0.095 g,0.736 mmol). The mixture was shaken at rt for 3 h. The crude reactionmixture was concentrated, redissolved in a mixture of MeOH and THF, andpurified by reverse phase preparative HPLC. The title compound wasisolated as a mono-TFA salt white solid (66 mg, 44% yield). LCMS: m/z699 (M+H⁺), retention time 3.03 min (method 11). ¹H NMR (400 MHz, 1:1mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.93 (s, 3H) 0.94 (s, 3H)1.01 (d, J=1.76 Hz, 6H) 1.07-1.20 (m, 5H) 1.21-1.28 (m, 1H) 1.34-1.57(m, 11H) 1.63-1.78 (m, 6H) 1.78-1.95 (m, 2H) 1.95-2.05 (m, 1H) 2.12 (dd,J=17.19, 6.40 Hz, 1H) 2.31-2.41 (m, 1H) 2.41-2.51 (m, 1H) 2.61 (td,J=10.98, 4.64 Hz, 1H) 3.90 (s, 3H) 4.56-4.59 (m, 1H) 4.64 (br. s., 1H)4.75 (d, J=1.51 Hz, 1H) 5.28 (dd, J=6.02, 1.51 Hz, 1H) 7.20 (m, J=8.28Hz, 2H) 7.53 (br. s., 1H) 7.70 (d, J=6.27 Hz, 1H) 7.90 (m, J=8.28 Hz,2H) 7.98 (t, J=7.78 Hz, 1H) 8.67 (br. s., 1H).

Step 2: Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(pyridin-2-ylmethylsulfonamido)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

In a 1 dram vial with PTFE lined screw cap were combined methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(pyridin-2-ylmethylsulfonamido)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.060 g, 0.086 mmol), lithium hydroxide monohydrate (0.022 g, 0.515mmol), 1,4-dioxane (0.8 mL) and water (0.4 mL). The vial was sealed andheated with stirring to 75° C. for 7 min. Small quantities of MeOH andTHF were added to completely dissolve all solids, and the mixture wasfiltered and purified by reverse phase preparative HPLC. The mono-TFAsalt product was isolated after purification as a white solid (56 mg,96% yield). LCMS: m/z 685 (M+H⁺), retention time 2.62 min (method 11).¹H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 0.94(s, 3H) 0.95 (s, 3H) 1.02 (d, J=2.14 Hz, 6H) 1.09-1.20 (m, 5H) 1.22-1.29(m, 1H) 1.29-1.40 (m, 1H) 1.40-1.60 (m, 9H) 1.65-1.80 (m, 6H) 1.82-2.02(m, 3H) 2.13 (dd, J=17.09, 6.41 Hz, 1H) 2.33-2.41 (m, 1H) 2.41-2.49 (m,1H) 2.64 (td, J=11.06, 4.73 Hz, 1H) 4.64 (s, 3H) 4.77 (d, J=1.53 Hz, 1H)5.29 (dd, J=6.26, 1.68 Hz, 1H) 7.20 (d, J=8.54 Hz, 2H) 7.61-7.67 (m, 1H)7.80 (d, J=7.93 Hz, 1H) 7.92 (d, J=8.24 Hz, 2H) 8.11 (td, J=7.78, 1.53Hz, 1H) 8.69 (d, J=3.97 Hz, 1H).

Section 5. Amines Example 132 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoropyridin-4-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoropyridin-4-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,HCl (318 mg, 0.548 mmol) in DCE (10 mL) was added glacial acetic acid(0.314 mL, 5.48 mmol), sodium acetate (67.4 mg, 0.822 mmol),2-fluoropyridine-4-carboxaldehyde (206 mg, 1.644 mmol) and 4 A molecularsieves. The reaction mixture was heated to 65° C. for 18 h. To thereaction mixture was added sodium triacetoxyhydroborate (581 mg, 2.74mmol) and the resulting mixture was heated to 65° C. for 7.5 h, then themixture was left at rt for 48 h. The reaction was diluted with DCM (50mL) and washed with saturated NaHCO₃ (20 mL). The aqueous layer wasextracted with DCM (2×25 mL). The combined organic layer was dried overMgSO₄, filtered and concentrated. The resulting dark brown residue wasdissolved in THF (3 mL) and MeOH (0.6 mL), filtered and purified byreverse phase preparative HPLC using HPLC method 3 to give methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoropyridin-4-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,TFA (218.4 mg, 0.285 mmol, 52.0% yield) as a white solid. LCMS: m/e653.4 (M+H)⁺, 2.69 min (method 6).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoropyridin-4-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoropyridin-4-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,TFA (77.7 mg, 0.101 mmol) in THF (3 mL) was added a 0.753 molar aqueoussolution of LiOH.H₂O (0.539 mL, 0.405 mmol). The reaction mixture washeated to 75° C. After 4 h, the reaction mixture was concentrated. Thecrude residue was dissolved in THF (1.5 mL) and MeOH (200 μL), filteredand purified by reverse phase preparative HPLC using HPLC method 3 togive4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoropyridin-4-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA (30.6 mg, 0.037 mmol, 36.1% yield) as a white solid. LCMS: m/e637.7 (M−H)⁻, 3.12 min (method 6). ¹H NMR (500 MHz, 1:1 CDCl₃:MeOD)δ=8.24 (d, J=5.2 Hz, 1H), 7.92 (d, J=8.2 Hz, 2H), 7.43 (d, J=5.2 Hz,1H), 7.24 (s, 1H), 7.20 (d, J=8.5 Hz, 2H), 5.29 (dd, J=1.7, 6.3 Hz, 1H),4.78 (s, 1H), 4.17 (br. s., 2H), 2.78-2.69 (m, 1H), 2.18-2.10 (m, 2H),2.09-2.01 (m, 2H), 1.98 (dd, J=3.1, 11.9 Hz, 1H), 1.96-1.88 (m, 1H),1.83-1.76 (m, 1H), 1.72 (s, 3H), 1.70-1.64 (m, 1H), 1.63-1.40 (m, 10H),1.39-1.31 (m, 1H), 1.31-1.23 (m, 2H), 1.13 (s, 3H), 1.07 (s, 3H), 1.02(s, 3H), 0.95 (s, 3H), 0.94 (s, 3H). ¹³C NMR (1:1 CDCl₃:MeOD) d ppm15.3, 16.6, 17.4, 19.5, 20.6, 21.8, 22.2, 26.1, 27.6, 29.0, 29.5, 30.2,33.9, 34.6, 37.2, 38.2, 38.4, 41.8, 42.8, 43.1, 45.7, 47.2, 49.7, 49.9,50.3, 50.5, 53.9, 78.8, 123.1, 123.2, 124.9, 129.3, 129.7, 131.0, 147.4,149.7, 164.0, 166.0, 170.1.

Example 133 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((5-fluoropyridin-2-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 47% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoropyridin-4-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 5-fluoro-2-formylpyridine was used instead of2-fluoropyridine-4-carboxaldehyde in Step 1. LCMS: m/e 639.5 (M+H)⁺,3.33 min (method 6). ¹H NMR (500 MHz, 1:1 CDCl₃:MeOD) δ=8.46 (d, J=2.7Hz, 1H), 7.93 (d, J=8.2 Hz, 2H), 7.68 (dt, J=2.7, 8.2 Hz, 1H), 7.53 (dd,J=4.1, 8.7 Hz, 1H), 7.21 (d, J=8.5 Hz, 2H), 5.31 (dd, J=1.7, 6.3 Hz,1H), 4.83 (s, 1H), 4.74 (s, 1H), 4.49 (d, J=15.3 Hz, 1H), 4.32 (d,J=15.0 Hz, 1H), 2.78 (dt, J=5.3, 10.9 Hz, 1H), 2.22-2.06 (m, 5H), 1.96(dt, J=3.4, 12.2 Hz, 1H), 1.89-1.82 (m, 1H), 1.80 (d, J=10.7 Hz, 2H),1.76 (s, 3H), 1.74-1.66 (m, 2H), 1.64-1.54 (m, 4H), 1.53-1.47 (m, 2H),1.46-1.42 (m, 1H), 1.41-1.37 (m, 1H), 1.33 (s, 3H), 1.29 (dd, J=3.8, 9.9Hz, 1H), 1.24 (dd, J=4.1, 13.0 Hz, 1H), 1.13 (s, 3H), 1.07 (s, 3H), 0.97(s, 3H), 0.95 (s, 3H).

Example 134 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((3-(trifluoromethyl)pyridin-2-yl)methylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared in 42% yield from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the same procedure as described for the preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoropyridin-4-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 3-trifluoromethylpyridine-2-carbaldehyde was used insteadof 2-fluoropyridine-4-carboxaldehyde in Step 1. LCMS: m/e 689.6 (M+H)⁺,4.12 min (method 6). ¹H NMR (500 MHz, 1:1 CDCl₃:MeOD) δ=8.83 (d, J=4.3Hz, 1H), 8.28 (d, J=7.9 Hz, 1H), 7.93 (d, J=8.5 Hz, 2H), 7.72 (dd,J=5.0, 7.8 Hz, 1H), 7.21 (d, J=8.5 Hz, 2H), 5.31 (dd, J=1.5, 6.1 Hz,1H), 4.85 (s, 1H), 4.76 (s, 1H), 4.44 (d, J=16.2 Hz, 1H), 2.80 (dt,J=5.5, 11.0 Hz, 1H), 2.25-2.10 (m, 5H), 2.02 (dt, J=3.5, 12.1 Hz, 1H),1.92-1.79 (m, 2H), 1.78 (s, 3H), 1.76-1.68 (m, 3H), 1.64-1.54 (m, 4H),1.52-1.43 (m, 3H), 1.40 (br. s., 1H), 1.36 (s, 3H), 1.32-1.22 (m, 2H),1.16-1.13 (m, 3H), 1.08 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H).

Example 135 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-hydroxyethylsulfonyl)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(vinylsulfonyl)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(30 mg, 0.055 mmol), TEA (0.023 mL, 0.165 mmol) and vinylsulfonylethene(19.5 mg, 0.165 mmol) in EtOH (1 mL) was heated for 3 h at 100° C. Thereaction mixture was quenched with water, extracted with DCM (3×2 mL).The organic phases were combined, dried over sodium sulfate, filteredand concentrated under reduced pressure to provide the title compound asa brown oil (25 mg, 68%). LCMS: m/e 662.42 (M+H)⁺, 3.45 min (method 10).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-hydroxyethylsulfonyl)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(vinylsulfonyl)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(25 mg, 0.038 mmol) and sodium hydroxide (0.189 mL, 0.189 mmol) indioxane (1 mL) was heated at 78° C. for 3 h. The reaction mixture wasfiltered and the clear solution was purified by prep HPLC to provide thetitle compound as a white solid (14 mg, 53%). LCMS: m/e 666.39 (M+H)⁺,2.48 min (method 10). ¹H NMR (500 MHz, Acetic acid d4) δ ppm 8.03 (d,J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.27 Hz, 1H), 4.87(s, 1H), 4.75 (s, 1H), 4.31-4.01 (m, 3H), 3.93-3.74 (m, 3H), 3.68-3.41(m, 2H), 3.06-2.73 (m, 1H), 2.48-1.26 (m, 22H), 1.76 (s, 3H), 1.23 (s,3H), 1.14 (s, 3H), 1.09 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).

Example 136 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(methylsulfonyl)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-hydroxyethylsulfonyl)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using methylsulfonylethene instead of vinylsulfonylethene inStep 1. The product was isolated as a white solid (6 mg, 39%). LCMS: m/e636.37 (M+H)⁺, 2.53 min (method 10). ¹H NMR (500 MHz, Acetic acid d4) δppm 8.04 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.44-5.33 (m, 1H),4.88 (s, 1H), 4.76 (s, 1H), 4.17-4.00 (m, 1H), 3.93-3.69 (m, 3H), 3.22(s, 3H), 3.00-2.85 (m, 1H), 2.40-1.26 (m, 22H), 1.77 (s, 3H), 1.23 (s,3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).

Example 137 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(600 mg, 1.10 mmol), 4-(2-chloroethyl)thiomorpholine 1,1-dioxide (600mg, 2.56 mmol) (prepared as described in WO2002045652), anhydrouspotassium phosphate (3.00 g, 14.1 mmol) and potassium iodide (10 mg,0.060 mmol) in acetonitrile (50 mL) was placed in 150 mL AceGlassresealable pressure vessel. The white suspension was blanketed withnitrogen. The vessel was sealed and warmed to 115-125° C. for 48 h. Thecrude reaction was filtered through a short bed of silica gel and washedwith ethyl acetate. The filtrate was concentrated in vacuo and purifiedby silica gel chromatography eluted with ethyl acetate and hexanes(0-50%) to afford the title compound as a colorless foam (566 mg, 73%).¹H NMR (500 MHz, CHLOROFORM-d) δ 7.95 (d, J=8.2 Hz, 2H), 7.22 (d, J=8.2Hz, 2H), 5.31 (d, J=4.6 Hz, 1H), 4.74 (d, J=1.8 Hz, 1H), 4.62 (s, 1H),3.93 (s, 3H), 3.22-2.99 (m, 9H), 2.79-2.55 (m, 4H), 2.52-2.42 (m, 1H),2.18-2.09 (m, 1H), 1.99-1.02 (m, 20H), 1.72 (s, 3H), 1.11 (s, 3H), 1.01(s., 3H), 1.10 (s, 3H), 0.95 (s, 3H), 0.95 (s., 3H).LCMS: m/e 705.51(M+H)⁺, 3.01 min (method 10).

Step 2. Preparation of4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxido-4-thiomorpholinyl)ethyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]-benzoicacid

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(500 mg, 0.709 mmol) and aqueous sodium hydroxide 10N (1.42 mL, 14.2mmol) in dioxane (10 mL) was heated at 78° C. for 3 h. The reaction wasfiltered and the resulting clear solution was purified by prep HPLC toprovide the title compound as white solid (200 mg, 39%). LCMS: m/e691.59 (M+H)⁺, 2.53 min (method 10). ¹H NMR (500 MHz, Acetic acid d4) δppm 8.04 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.45-5.34 (m, 1H),4.85 (s, 1H), 4.74 (s, 1H), 3.55-3.40 (m, 1H), 3.39-3.22 (m, 6H),3.22-3.11 (m, 4H), 3.11-3.03 (m, 1H), 3.04-2.94 (m, 1H), 2.36-1.18 (m,22H), 1.76 (s, 3H), 1.30 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s,3H), 1.00 (s, 3H).

Example 138 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(tert-butoxycarbonylamino)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(tert-butoxycarbonylamino)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(1.00 g, 1.84 mmol) in DCE (5 mL) was added tert-butyl2-oxoethylcarbamate (1.17 g, 7.36 mmol) and tetraisopropoxytitanium(0.700 mL, 2.39 mmol). The reaction mixture was stirred for 1 h, thensodium triacetoxyborohydride (1.17 g, 5.52 mmol) was added. The reactionmixture was stirred for 18 h. The reaction mixture was quenched withsodium bicarbonate and was extracted with DCM (3×40 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by silica gelchromatography using ethyl acetate and hexanes (20-100%) as the eluentto provide the title compound as a pale yellow oil. (900 mg, 71%). LCMS:m/e 688.24 (M+H)⁺, 2.51 min (method 11).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(tert-butoxycarbonylamino)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the hydrolysis methoddescribed above for the synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-hydroxyethylsulfonyl)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(tert-butoxycarbonylamino)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(10 mg, 0.015 mmol) as starting material. The title compound wasisolated as a white solid (4 mg, 39%). LCMS: m/e 673.45 (M+H)⁺, 2.65 min(method 10). ¹H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (d, J=8.24 Hz,2H), 7.30 (d, J=8.55 Hz, 2H), 5.51-5.32 (m, 1H), 4.87 (s, 1H), 4.75 (s,1H), 3.82-3.53 (m, 1H), 3.53-3.24 (m, 3H), 3.04-2.83 (m, 1H), 2.37-1.15(m, 22H), 1.77 (s, 3H), 1.53-1.49 (m, 9H), 1.27 (s, 3H), 1.14 (s, 3H),1.11 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).

Example 139 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-aminoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-aminoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(tert-butoxycarbonylamino)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(900 mg, 1.310 mmol) in dioxane (1 mL) was added HCl (4M in dioxane)(4.26 mL, 17.03 mmol) and the reaction mixture was stirred for 4 h atrt. The reaction mixture was concentrated under reduced pressure toprovide the title compound as a brown solid (769 mg, 100%). LCMS: m/e588.08 (M+H)⁺, 2.44 min (method 11).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-aminoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the hydrolysis methoddescribed above for the synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-hydroxyethylsulfonyl)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-aminoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(4 mg, 0.006 mmol) as starting material. The title compound was isolatedas a white solid (2.4 mg, 67%). LCMS: m/e 573.2 (M+H)⁺, 2.39 min (method10). ¹H NMR (500 MHz, Acetic acid d4) δ ppm 8.03 (d, J=8.24 Hz, 2H),7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.27 Hz, 1H), 4.87 (s, 1H), 4.76 (s,1H), 3.80-3.68 (m, 3H), 3.68-3.59 (m, 1H), 2.97-2.80 (m, 1H), 2.38-1.21(m, 22H), 1.78 (s, 3H), 1.20 (s, 3H), 1.14 (s, 3H), 1.09 (s, 3H), 1.01(s, 3H), 1.00 (s, 3H).

Examples 140 and 141 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-carboxyethylamino)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid and3,3′-(2-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-carboxyphenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-ylamino)ethylazanediyl)dipropanoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(3-methoxy-3-oxopropylamino)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoateand dimethyl3,3′-(2-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-ylamino)ethylazanediyl)dipropanoate

Methyl acrylate (9.97 mg, 0.116 mmol) was added to a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-aminoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(34 mg, 0.058 mmol) in MeOH (2 mL) and the mixture was stirred for 16 hat room temperature. The reaction mixture was concentrated under reducedpressure to provide a mixture of the two title compounds as a brown oil(20 mg, 51%). LCMS: m/e 673.47 (M+H)⁺, 2.96 min and 759.51 (M+H)⁺, 3.43min (method 10). The mixture was taken to the next step without furtherpurification.

Step 2. Ester Hydrolysis

The mixture of esters from above (20 mg) in dioxane (1 mL) was treatedwith sodium hydroxide (0.297 mL, 0.297 mmol) at 78° C. for 3 hours. Thereaction mixture was filtered and purified by prep. HPLC to provide thefollowing two compounds:

Example 1404-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-carboxyethylamino)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

White solid (16 mg, 43% over 2 steps). LCMS: m/e 645.44 (M+H)⁺, 2.37 min(method 10). ¹H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (d, J=8.2 Hz,2H), 7.30 (d, J=8.5 Hz, 2H), 5.37 (d, J=4.6 Hz, 1H), 4.87 (s, 1H), 4.75(s, 1H), 3.78 (s., 2H), 3.77-3.59 (m, 2H), 3.45 (t, J=6.4 Hz, 2H), 2.90(t, J=6.4 Hz, 2H), 2.87-2.72 (m, 1H), 2.42-1.22 (m, 22H), 1.78 (s, 3H),1.20 (s, 3H), 1.13 (s, 3H), 1.09 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).

Example 1413,3′-(2-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-carboxyphenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-ylamino)ethylazanediyl)dipropanoicacid

White solid (5.7 mg, 57% over 2 steps). LCMS: m/e 717.51 (M+H)⁺, 2.25min (method 10). ¹H NMR (500 MHz, Acetic acid d4) δ ppm 8.03 (d, J=8.2Hz, 2H), 7.29 (d, J=8.2 Hz, 2H), 5.36 (d, J=4.9 Hz, 1H), 4.88 (s, 1H),4.76 (s, 1H), 3.83-3.66 (m, 4H), 3.51 (t, J=6.3 Hz, 4H), 2.93 (t, J=6.9Hz, 4H), 2.88-2.74 (m, 1H), 2.42-1.22 (m, 22H), 1.78 (s, 3H), 1.19 (s,3H), 1.14 (s, 3H), 1.08 (s, 3H), 1.01 (s, 3H), 0.99 (s, 3H).

Example 142 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(3-(dimethylamino)-3-oxopropylamino)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-carboxyethylamino)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using N,N-dimethylacrylamide as the Michael aceptor reagent in thefirst step. The product was isolated as a white solid (9 mg, 50%). LCMS:m/e 672.47 (M+H)⁺, 2.33 min (method 2). ¹H NMR (500 MHz, Acetic acid d4)δ ppm 8.04 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.37 (d, J=4.6 Hz,1H), 4.88 (s, 1H), 4.76 (s, 1H), 3.86-3.59 (m, 4H), 3.51-3.37 (m, 2H),3.07 (s, 3H), 2.99 (s, 3H), 2.95 (t, J=5.6 Hz, 2H), 2.90-2.76 (m, 1H),2.37-1.22 (m, 22H), 1.78 (s, 3H), 1.20 (s, 3H), 1.14 (s, 3H), 1.09 (s,3H), 1.02 (s, 3H), 1.00 (s, 3H).

Example 142 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(tert-butoxycarbonylamino)propylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(tert-butoxycarbonylamino)propylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

Acetic acid (0.013 mL, 0.221 mmol) and tert-butyl 3-oxopropylcarbamate(38.2 mg, 0.221 mmol) were added to a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(40 mg, 0.074 mmol) in EtOH (1 mL) and dioxane (1.0 mL) and the mixturewas stirred for 2 h at rt. Sodium triacetoxyborohydride (78 mg, 0.368mmol) was added and the reaction mixture was stirred at 20° C. for twohours. The reaction was quenched with a saturated aqueous solution ofsodium bicarbonate (3 mL), washed with 0.1N HCl (5 mL) and brine (5 mL)and extracted with DCM (3×5 mL). All the extracts were combined, driedover sodium sulfate, filtered and concentrated under reduced pressure toprovide the title compound as pale yellow oil (28 mg, 54%). LCMS: m/e701.51 (M+H)⁺, 4.0 min (method 10).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(tert-butoxycarbonylamino)propylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the hydrolysis methoddescribed above for the synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-hydroxyethylsulfonyl)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(tert-butoxycarbonylamino)propylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(5 mg, 0.007 mmol) as starting material. The title compound was isolatedas a white solid (3 mg, 58%). LCMS: m/e 687.54 (M+H)⁺, 2.69 min (method10). ¹H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (d, J=8.24 Hz, 2H),7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.58 Hz, 1H), 4.87 (s, 1H), 4.74 (s,1H), 3.38-3.17 (m, 4H), 3.04-2.86 (m, 1H), 2.36-1.17 (m, 24H), 1.77 (s,3H), 1.50 (s, 9H), 1.25 (s, 3H), 1.14 (s, 3H), 1.09 (s, 3H), 1.02 (s,3H), 1.00 (s, 3H).

Example 144 Preparation of4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[3-(1,1-dioxido-4-thiomorpholinyl)propyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]-benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-aminopropylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

4.0M HCl in dioxane (32.8 μl, 0.131 mmol) was added to a solution ofmethyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(tert-butoxycarbonylamino)propylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(23 mg, 0.033 mmol) in dioxane (1 mL) and the mixture was stirred for 6h at room temperature. The reaction mixture was concentrated underreduced pressure to provide the title compound as a brown oil (15 mg,76%). LCMS: m/e 601.48 (M+H)⁺, 2.88 min (method 10).

Step 2. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(1,1-dioxido-4-thiomorpholinyl)propyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Vinylsulfonylethene (5.90 mg, 0.050 mmol) and triethylamine (6.96 μl,0.050 mmol) were added to a mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-aminopropylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(15 mg, 0.025 mmol) in EtOH (1 mL). The reaction mixture was heated to100° C. for 3 hours. The reaction mixture was concentrated under reducedpressure to provide the desired product as a brown solid (15 mg, 76%).LCMS: m/e 719.46 (M+H)⁺, 3.68 min (method 10).

Step 3. Preparation of,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[3-(1,1-dioxido-4-thiomorpholinyl)propyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]-benzoicacid

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(1,1-dioxido-4-thiomorpholinyl)propyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (15 mg, 0.021 mmol) and 1N sodium hydroxide (0.104 mL, 0.104 mmol)in dioxane (1 mL) was heated at 78° C. for 3 hours. The reaction mixturewas purified by prep HPLC to provide the title compound as a white solid(9 mg, 58%). LCMS: m/e 705.49 (M+H)⁺, 2.60 min (method 10). ¹H NMR (400MHz, Acetic acid d4) δ ppm 7.99 (d, J=8.28 Hz, 2H), 7.25 (d, J=8.28 Hz,2H), 5.33 (d, J=4.77 Hz, 1H), 4.82 (s, 1H), 4.71 (s, 1H), 3.87 (br. s.,4H), 3.56 (d, J=4.27 Hz, 4H), 3.51-3.40 (m, 2H), 3.39-3.22 (m, 2H),2.86-2.69 (m, 1H), 2.57-2.34 (m, 2H), 2.27-1.18 (m, 22H), 1.72 (s, 3H),1.16 (s, 3H), 1.10 (s, 3H), 1.04 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H).

Example 145 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(50 mg, 0.092 mmol), 2-chloro-N,N-dimethylacetamide (33.5 mg, 0.276mmol), potassium phosphate (78 mg, 0.368 mmol) and potassium iodide(36.6 mg, 0.221 mmol) in acetonitrile (1 mL) was heated at 120° C. for33 h in a sealed tube. The reaction mixture was quenched with distilledwater (5 mL) and extracted with DCM (3×5 mL). The combined organiclayers were dried over sodium sulfate, filtered and concentrated underreduced pressure to provide the title compound as a pale yellow solid(30 mg, 52%). LCMS: m/e 629.51 (M+H)⁺, 3.03 min (method 10). The productwas used in the next step without further purification.

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(30 mg, 0.048 mmol) and aqueous 1N sodium hydroxide (0.048 mL, 0.048mmol) in dioxane (1 mL) was heated up at 78° C. for 3 h. The reactionmixture was filtered and the clear solution was purified by prep HPLC toprovide the title compound as a white solid (9.5 mg, 31%). LCMS: m/e615.56 (M+H)⁺, 2.52 min (method 10). ¹H NMR (500 MHz, Acetic acid d4) δppm 8.04 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.38 (d, J=4.58Hz, 1H), 4.89 (s, 1H), 4.76 (s, 1H), 4.52 (d, J=16.17 Hz, 1H), 4.04 (d,J=16.17 Hz, 1H), 3.08 (d, J=10.99 Hz, 6H), 3.01-2.86 (m, 1H), 2.37-1.22(m, 22H), 1.79 (s, 3H), 1.30 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.03(s, 3H), 1.00 (s, 3H).

Example 146 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(2-oxopyrrolidin-1-yl)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 1-(2-chloroethyl)pyrrolidin-2-one as the alkylating reagentin Step 1. The product was isolated as a white solid (19 mg, 62%). LCMS:m/e 641.57 (M+H)⁺, 2.58 min (method 10). ¹H NMR (500 MHz, Acetic acidd4) δ ppm 8.04 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.55 Hz, 2H), 5.37 (d,J=4.88 Hz, 1H), 4.91 (s, 1H), 4.76 (s, 1H), 3.89-3.73 (m, 2H), 3.72-3.56(m, 3H), 3.55-3.45 (m, 1H), 2.93-2.80 (m, 1H), 2.57 (td, J=8.24, 3.97Hz, 2H), 2.34-1.19 (m, 24H), 1.78 (s, 3H), 1.23 (s, 3H), 1.13 (s, 3H),1.10 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).

Example 147 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-oxo-2-(pyrrolidin-1-yl)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 2-chloro-1-(pyrrolidin-1-yl)ethanone as the alkylatingreagent in Step 1. The product was isolated as a white solid (19 mg,46%). LCMS: m/e 641.46 (M+H)⁺, 2.55 min (method 10). ¹H NMR (500 MHz,Acetic acid d4) δ ppm 8.04 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H),5.38 (d, J=4.58 Hz, 1H), 4.89 (s, 1H), 4.76 (s, 1H), 4.43 (d, J=16.48Hz, 1H), 3.99 (d, J=16.17 Hz, 1H), 3.73-3.42 (m, 4H), 3.15-2.86 (m, 1H),2.41-1.19 (m, 26H), 1.79 (s, 3H), 1.28 (s, 3H), 1.14 (s, 3H), 1.10 (s,3H), 1.03 (s, 3H), 1.00 (s, 3H).

Example 148 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(methylamino)-2-oxoethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 2-chloro-N-methylacetamide as the alkylating reagent inStep 1. The product was isolated as a white solid (41 mg, 80%). LCMS:m/e 601.45 (M+H)⁺, 2.31 min (method 11). ¹H NMR (500 MHz, Acetic acidd4) δ ppm 8.04 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.38 (d,J=4.58 Hz, 1H), 4.88 (s, 1H), 4.76 (s, 1H), 4.24 (d, J=15.56 Hz, 1H),3.92 (d, J=15.26 Hz, 1H), 2.88 (s, 3H), 3.08-2.74 (m, 1H), 2.31-1.30 (m,22H), 1.78 (s, 3H), 1.29 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.03 (s,3H), 1.01 (s, 3H).

Example 149 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(diethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 2-chloro-N,N-diethylacetamide as alkylating reagent inStep 1. The product was isolated as a white solid (20 mg, 39%). LCMS:m/e 643.50 (M+H)⁺, 2.35 min (method 11). ¹H NMR (400 MHz, CHLOROFORM-d)δ ppm 7.99 (d, J=8.28 Hz, 2H), 7.24 (d, J=8.28 Hz, 2H), 5.31 (d, J=4.52Hz, 1H), 4.74 (d, J=1.76 Hz, 1H), 4.60 (s, 1H), 3.58-3.21 (m, 6H),2.82-2.69 (m, 1H), 2.22-1.02 (m, 28H), 1.72 (s, 3H), 1.18 (s, 3H), 1.01(s, 3H), 1.00 (s, 3H), 0.95 (s, 6H).

Example 150 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(isopropylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 2-chloro-N-isopropylacetamide as the alkylating reagent inStep 1. The product was isolated as a white solid (50 mg, 81%). LCMS:m/e 629.46 (M+H)⁺, 2.60 min (method 10). ¹H NMR (400 MHz, Acetic acidd4) δ ppm 7.99 (d, J=8.53 Hz, 2H), 7.26 (d, J=8.53 Hz, 2H), 5.34 (d,J=4.77 Hz, 1H), 4.84 (s, 1H), 4.72 (s, 1H), 4.15 (d, J=15.31 Hz, 1H),4.06 (dt, J=13.11, 6.62 Hz, 1H), 3.85 (d, J=15.31 Hz, 1H), 3.07-2.77 (m,1H), 2.41-1.26 (m, 22H), 1.74 (s, 3H), 1.24 (s, 3H), 1.16 (d, J=6.53 Hz,6H), 1.10 (s, 3H), 1.06 (s, 3H), 0.99 (s, 3H), 0.97 (s, 3H).

Example 151 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-hydroxyethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(tert-butyldimethylsilyloxy)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(300 mg, 0.552 mmol) in DCE (4 mL) was added(tert-butyldimethylsilyloxy)acetaldehyde (131 mL, 0.690 mmol) andtitanium(IV) isopropoxide (0.202 mL, 0.690 mmol). The mixture wasstirred at rt for 45 minutes and sodium triacetoxyborohydride (234 mg,1.103 mmol) was added. The mixture was stirred at rt for 23 h and anadditional 0.1 mL of (tert-butyldimethylsilyloxy)acetaldehyde and anadditional 150 mg of sodium triacetoxyborohydride were added. Themixture was stirred at rt for an additional 22 h, then was diluted with15 mL of sat. NaHCO₃ and was extracted with dichloromethane (3×15 mL).The combined organic layers were dried with Na₂SO₄, the drying agent wasremoved by filtration and the filtrate was concentrated under reducedpressure. The residue was adsorbed to silica gel and was purified byflash chromatography using a 0-10% EtOAc in hexanes gradient. Thefractions containing the expected product were combined and wereconcentrated under reduced pressure to give the title compound (0.211 g,0.301 mmol, 54.5% yield) as a clear yellow film. The product was used inthe next step with no additional purification. LCMS: m/e 702.7 (M+H)⁺,2.35 min (method 2).

Step 2. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-hydroxyethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(tert-butyldimethylsilyloxy)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.211 g, 0.301 mmol) in THF (2 mL) was added TBAF (1M in THF) (0.601mL, 0.601 mmol). The mixture was stirred at rt for 2.75 h then wasdiluted with water (10 mL) and was extracted with dichloromethane (3×10mL). The combined organic layers were dried with Na₂SO₄, the dryingagent was removed by filtration and the filtrate was concentrated underreduced pressure. The residue was adsorbed to silica gel and waspurified by flash chromatography using a 0-25% EtOAc in hexanesgradient. The title compound (93.4 mg, 0.159 mmol, 52.9% yield), wasisolated as a colorless film. LCMS: m/e 588.6 (M+H)⁺, 1.98 min (method2). ¹H NMR (500 MHz, CHLOROFORM-d) d ppm 7.91 (d, J=8.24 Hz, 2H), 7.18(d, J=8.24 Hz, 2H), 5.27 (d, J=4.58 Hz, 1H), 4.70 (d, J=1.83 Hz, 1H),4.59 (s, 1H), 3.89 (s, 3H), 3.54-3.64 (m, 2H), 2.52-2.69 (m, 3H), 2.09(dd, J=17.09, 6.41 Hz, 1H), 1.68 (s, 3H), 1.07 (s, 3H), 0.98 (s, 3H),0.97 (s, 3H), 0.93-2.05 (m, 21H), 0.91 (s, 3H), 0.91 (s, 3H).

Step 3. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-hydroxyethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-hydroxyethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(35 mg, 0.060 mmol) in dioxane (1 mL) was added NaOH (1N) (0.298 mL,0.298 mmol). The mixture was heated to 85° C. for 15 h then was cooledto rt. The mixture was diluted with MeOH and was purified by prep HPLC.The fractions containing the expected product were combined andconcentrated under reduced pressure to give the title compound (25 mg,0.041 mmol, 69.5% yield) as a white solid. LCMS: m/e 574.5 (M+H)⁺, 1.69min (method 2). ¹H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (2H, d,J=8.2 Hz), 7.30 (2H, d, J=8.2 Hz), 5.37 (1H, d, J=4.6 Hz), 4.86 (1H, s),4.75 (1H, s), 3.95-4.11 (2H, m), 3.25-3.43 (2H, m), 2.90-2.98 (1H, m),1.77 (3H, s), 1.21 (3H, s), 1.14 (3H, s), 1.09 (3H, s), 1.02 (3H, s),1.00 (3H, s), 0.97-2.32 (22H, m).

Example 152 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(cyclopropylmethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(cyclopropylmethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.022 g, 0.040 mmol) in DCE (0.25 mL) was addedcyclopropanecarbaldehyde (2.84 mg, 0.040 mmol) and titanium (IV)isopropoxide (0.015 mL, 0.051 mmol). The mixture was stirred at rt for 1h and sodium triacetoxyborohydride (0.017 g, 0.081 mmol) was added.After stirring the mixture for 16.75 h, the mixture was diluted with 3mL of water and was filtered through a pad of celite, then was extractedwith dichloromethane (3×4 mL). The combined organic layers were driedwith Na₂SO₄. The drying agent was removed by filtration and the filtratewas concentrated under reduced pressure to give the title compound(0.024 g, 0.040 mmol, 99% yield) as a clear film. The crude product wasused in the next step with no additional purification. LCMS: m/e 598.6(M+H)⁺, 2.13 min (method 2).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(cyclopropylmethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a cloudy mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(cyclopropylmethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.024 g, 0.040 mmol) in 1,4-dioxane (1.5 mL) was added NaOH (1N) (0.5mL, 0.5 mmol). The mixture was heated to 65° C. After two hours, themixture was cooled to rt and stirred at rt overnight. The mixture wasfiltered through plug of glass wool and was purified by prep HPLC toafford the title compound (0.007 g, 10.79 μmol, 26.9% yield) as a whitefilm. LCMS: m/e 584.6 (M+H)⁺, 1.83 min (method 2). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 8.00 (2H, d, J=8.0 Hz), 7.21 (2H, d, J=8.0 Hz), 5.31(1H, d, J=5.0 Hz), 4.75 (1H, d, J=1.5 Hz), 4.61 (1H, s), 2.76 (1H, td,J=10.9, 5.6 Hz), 2.62 (1H, dd, J=11.2, 6.1 Hz), 2.23 (1H, dd, J=11.5,7.8 Hz), 1.97-2.16 (3H, m), 1.82-1.95 (2H, m), 1.70 (3H, s), 1.16 (3H,s), 1.01 (3H, s), 1.00 (3H, s), 0.96 (3H, s), 0.95 (3H, s), 0.80-1.77(19H, m), 0.48-0.58 (2H, m), 0.09-0.24 (2H, m).

Example 153 Preparation of tert-butyl3-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-ylamino)methyl)piperidine-1-carboxylate

Step 1. Preparation of tert-butyl3-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-ylamino)methyl)piperidine-1-carboxylate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(30 mg, 0.055 mmol) in DCE (0.5 mL) was added3-formyl-piperidine-1-carboxylic acid tert-butyl ester (14.71 mg, 0.069mmol) and titanium(IV) isopropoxide (0.020 mL, 0.069 mmol). The mixturewas stirred at rt for 1 h and sodium triacetoxyborohydride (23.38 mg,0.110 mmol) was added. After stirring the mixture for 16.5 h, themixture was diluted with 3 mL of sat. NaHCO₃ and was extracted withdichloromethane (3×5 mL). The combined organic layers were dried withNa₂SO₄. The drying agent was removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was adsorbed to silicagel and was purified by silica gel flash chromatography using a 0-10%EtOAc in hexanes gradient and a Thomson 12 g silica gel column. Thefractions containing the expected product were combined and concentratedunder reduced pressure to afford the title compound (29 mg, 0.039 mmol,70.9% yield) as an off-white film. The product was used in the next stepwith no additional purification. LCMS: m/e 741.7 (M+H)⁺, 3.76 min(method 2).

Step 2. Preparation of tert-butyl3-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-ylamino)methyl)piperidine-1-carboxylate

To a solution of tert-butyl3-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-ylamino)methyl)piperidine-1-carboxylate(0.029 g, 0.039 mmol) in dioxane (2 mL) was added NaOH (1N) (0.196 mL,0.196 mmol). The mixture was heated to 85° C. overnight. After heatingthe mixture for 22 h, it was cooled to rt, diluted with MeOH, andpurified by prep HPLC to afford the title compound (24 mg, 0.031 mmol,80% yield) as a clear, colorless film. LCMS: m/e 727.7 (M+H)⁺, 2.00 min(method 2). ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.98 (2H, d, J=7.9 Hz),7.21 (2H, d, J=7.9 Hz), 5.29 (1H, d, J=5.5 Hz), 4.70 (1H, br. s.), 4.58(1H, br. s.), 3.83-4.22 (4H, m), 2.46-2.85 (4H, m), 2.29 (2H, br. s.),1.68 (3H, s), 1.47 (9H, d, J=4.6 Hz), 1.10 (3H, d, J=7.9 Hz), 0.98 (6H,br. s.), 0.93 (3H, s), 0.92 (3H, s), 0.77-2.15 (25H, m).

Example 154 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(piperidin-3-ylmethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a solution of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1-(tert-butoxycarbonyl)piperidin-3-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (0.019 g, 0.026 mmol) in DCM (1 mL) was added TFA (0.25 mL, 3.24mmol). The mixture was stirred at rt for 1.75 h. Then, the mixture wasconcentrated under reduced pressure and purified by prep HPLC to givethe title compound (14.2 mg, 0.021 mmol, 81% yield) as a white solid.LCMS: m/e 627.6 (M+H)⁺, 1.50 min (method 2). ¹H NMR (500 MHz, Aceticacid d4) δ ppm 8.04 (2H, d, J=8.2 Hz), 7.30 (2H, d, J=7.9 Hz), 5.37 (1H,s), 4.85 (1H, d, J=5.5 Hz), 4.75 (1H, s), 2.98-3.83 (6H, m), 2.82-2.91(1H, m), 2.57-2.72 (1H, m), 0.85-2.33 (44H, m).

Example 155 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(furan-2-ylmethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(furan-2-ylmethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(30 mg, 0.055 mmol) in DCE (0.5 mL) was added furfural (5.71 μL, 0.069mmol) and titanium(IV) isopropoxide (0.020 mL, 0.069 mmol). The mixturewas stirred at rt for 1 h and sodium triacetoxyborohydride (23.38 mg,0.110 mmol) was added. After stirring the mixture for 16 h at rt anadditional 5 μL of furfural was added along with an additional 0.025 gof sodium triacetoxborohydride. After stirring the mixture overnight atrt, it was purified by passing through a plug of silica gel and washingwith 0-25% EtOAc in hexanes. The fractions containing the product werecombined and concentrated under reduced pressure to give the titlecompound (31 mg, 0.050 mmol, 90% yield) as a light-yellow film. Theproduct was used in the next step with no additional purification. LCMS:m/e 625.6 (M+H)⁺, 3.08 min (method 2).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(furan-2-ylmethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(furan-2-ylmethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(31 mg, 0.050 mmol) in 1,4-dioxane (2 mL) was added 1N NaOH (0.248 mL,0.248 mmol). The mixture was heated to 85° C. for 22 h then was cooledto rt. The crude product was purified by prep HPLC. The fractionscontaining the expected product were combined and were concentratedunder reduced pressure to afford the title compound (19.3 mg, 0.030mmol, 60.5% yield) as a clear film. LCMS: m/e 610.69 (M+H)⁺, 2.35 min(method 2). ¹H NMR (400 MHz, CHLOROFORM-d) d ppm 8.00 (d, J=7.78 Hz,2H), 7.37 (d, J=1.00 Hz, 1H), 7.23 (d, J=7.78 Hz, 2H), 6.33 (dd, J=3.14,1.88 Hz, 1H), 6.21 (d, J=2.76 Hz, 1H), 5.53 (br. s., 1H), 5.29-5.34 (m,1H), 4.72 (d, J=1.76 Hz, 1H), 4.60 (s, 1H), 3.67 (s, 2H), 2.64 (td,J=10.85, 5.40 Hz, 1H), 1.71 (s, 3H), 1.10-1.15 (m, 3H), 1.01 (s, 3H),1.00 (s, 3H), 0.97-2.18 (m, 22H), 0.96 (s, 6H).

Example 156 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2,2-dimethoxyethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2,2-dimethoxyethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,HCl (0.9 g, 1.551 mmol) in DCM (Volume: 15 mL) was added glyoxal1,1-dimethyl acetal solution (45% in MTBE) (0.498 mL, 1.939 mmol),acetic acid (0.178 mL, 3.10 mmol), and sodium triacetoxyborohydride(0.493 g, 2.326 mmol). The mixture was stirred at rt. After 4 h ofstirring, an additional 0.5 mL of glyoxal 1,1-dimethyl acetal solution(45% in MTBE) was added along with an additional 0.5 g of sodiumtriacetoxyborohydride. After a total of 7 h of stirring, the mixture wasdiluted with 25 mL of sat. NaHCO₃ and was extracted with dichloromethane(3×25 mL). The combined organic layers were dried with Na₂SO₄. Thedrying agent was removed by filtration and the filtrate was concentratedunder reduced pressure. The residue was adsorbed to silica gel and waspurified by flash chromatography using a 0-10% EtOAc in hexanes gradientto give the title compound (0.67 g, 1.060 mmol, 68.4% yield) as a whitefoam. LCMS: m/e 632.75 (M+H)⁺, 2.45 min (method 11).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2,2-dimethoxyethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2,2-dimethoxyethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.025 g, 0.040 mmol) in 1,4-dioxane (1 mL) was added NaOH (1N) (0.198mL, 0.198 mmol). The mixture was heated to 85° C. After 6 h of heating,the mixture was cooled to rt, the reaction mixture was diluted with MeOHand was purified by prep HPLC. The fractions containing the expectedproduct were combined and were concentrated under reduced pressure togive the title compound (17 mg, 0.026 mmol, 66.1% yield) as a clearfilm. LCMS: m/e 618.8 (M+H)⁺, 2.28 min (method 11). ¹H NMR (500 MHz,CHLOROFORM-d) d ppm 7.99 (d, J=7.93 Hz, 2H), 7.20 (d, J=7.93 Hz, 2H),5.28 (d, J=4.88 Hz, 1H), 5.12 (br. s., 1

H), 4.72 (s, 1H), 4.58 (s, 1H), 4.53 (t, J=5.49 Hz, 1H), 3.44 (s, 3H),3.41 (s, 3H), 2.64-2.74 (m, 2H), 2.60 (dd, J=11.44, 6.56 Hz, 1H),1.97-2.13 (m, 2H), 1.86-1.95 (m, 2H), 1.81 (dd, J=12.51, 8.24 Hz, 1H),1.68 (s, 3H), 1.11 (s, 3H), 0.98 (s, 3H), 0.97 (br. s., 3H), 0.95-1.72(m, 17H), 0.93 (br. s., 6H).

Example 157 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-carboxycyclopropyl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(ethoxycarbonyl)cyclopropyl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3α-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(30 mg, 0.055 mmol) in DCE (0.5 mL) was added ethyl2-formyl-1-cyclopropanecarboxylate (9.13 mL, 0.069 mmol) andtitanium(IV) isopropoxide (0.020 mL, 0.069 mmol). The mixture wasstirred at rt for 1 h and sodium triacetoxyborohydride (23.38 mg, 0.110mmol) was added. After stirring the mixture for 16.25 h additional ethyl2-formyl-1-cyclopropanecarboxylate (9.13 mL, 0.069 mmol) and sodiumtriacetoxyborohydride (23.38 mg, 0.110 mmol) were added and the mixturewas again stirred at rt for 24 h. The reaction mixture was loadeddirectly onto a silica gel column and was purified by flashchromatography using a 0-25% EtOAc in hexanes gradient. The fractionscontaining the expected product were combined and concentrated underreduced pressure to give methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(ethoxycarbonyl)cyclopropyl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(33 mg, 0.049 mmol, 89% yield). LCMS: m/e 670.8 (M+H)⁺, 2.47 min (method11).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-carboxycyclopropyl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(ethoxycarbonyl)cyclopropyl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(33 mg, 0.049 mmol) in 1,4-dioxane (2 mL) was added NaOH (1N) (0.246 mL,0.246 mmol). The mixture was heated to 85° C. for 22 h then was cooledto rt. An additional 0.25 mL of 1N NaOH was added to the mixture and itwas again heated to 85° C. After stirring the mixture over the weekend,the reaction mixture was purified by prep HPLC. The fractions containingthe expected product were combined and concentrated under reducedpressure. ¹H NMR still showed impurities present, so the mixture waspurified a second time by prep HPLC. The fractions containing theproduct were combined and concentrated under reduced pressure to givethe title compound (8.3 mg, 0.012 mmol, 24.15% yield) as a white solid.LCMS: m/e 628.6 (M+H)⁺, 1.66 min (method 2).

Example 158 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(thiophen-3-ylmethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(thiophen-3-ylmethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(30 mg, 0.055 mmol) in DCE (0.5 mL) was added 3-thiophenecarboxaldehyde(7.73 mg, 0.069 mmol) and titanium(IV) isopropoxide (0.020 mL, 0.069mmol). The mixture was stirred at rt for 1 h and sodiumtriacetoxyborohydride (23.38 mg, 0.110 mmol) was added. The mixture wasstirred for 18 h at rt. The reaction mixture was loaded directly onto asilica gel column and was purified by flash chromatography using a 0-25%EtOAc in hexanes gradient. The fractions containing the expected productwere combined and were concentrated under reduced pressure to give thetitle compound (32 mg, 0.05 mmol, 91% yield). LCMS: m/e 640.6 (M+H)⁺,2.13 min (method 2).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(thiophen-3-ylmethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(thiophen-3-ylmethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(32 mg, 0.050 mmol) in dioxane (1 mL) was added NaOH (1N) (0.250 mL,0.250 mmol). The mixture was heated to 85° C. for 15 h. The mixture wascooled to rt and was purified by prep HPLC to give the title compound(18 mg, 0.027 mmol, 53.5% yield) as a white solid. LCMS: m/e 626.5(M+H)⁺, 1.82 min (method 2). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.00(2H, d, J=8.3 Hz), 7.30 (1H, dd, J=4.8, 3.0 Hz), 7.24 (2H, d, J=8.3 Hz),7.20 (1H, d, J=2.0 Hz), 7.12 (1H, dd, J=5.0, 1.0 Hz), 5.30-5.34 (1H, m),4.72 (1H, d, J=1.8 Hz), 4.61 (1H, s), 2.61 (1H, td, J=10.7, 5.4 Hz),1.89-2.17 (5H, m), 1.77-1.88 (1H, m), 1.72 (3H, s), 1.14 (3H, s), 1.02(3H, s), 1.00 (3H, s), 0.94-1.74 (18H, m), 0.96 (6H, s).

Example 159 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 4-(2-chloroethyl)morpholine hydrochloride as the alkylatingagent in Step 1. The product was isolated as a white solid (65 mg,49.4%). LCMS: m/e 643.6 (MH⁺), 2.35 min (method 13). ¹H NMR (400 MHz,MeOD) δ ppm 7.95 (m, J=8.3 Hz, 2H), 7.24 (m, J=8.3 Hz, 2H), 5.31 (d,J=4.8 Hz, 1H), 4.86 (s, 1H), 4.74 (s, 1H), 3.82-3.99 (m, 4H), 3.37-3.58(m, 4H), 3.21 (d, J=4.5 Hz, 2H), 3.19 (br. s., 2H), 2.67-2.86 (m, 1H),2.02-2.26 (m, 5H), 1.83-1.90 (m, 1H), 1.64-1.81 (m, 8H), 1.45-1.64 (m,7H), 1.34-1.45 (m, 2H), 1.27-1.34 (m, 1H), 1.15-1.27 (m, 4H), 1.12 (s,3H), 1.04 (s, 3H), 0.99 (s, 3H), 0.93 (s, 3H).

Example 160 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(bis(2-morpholinoethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was obtained as a side product in the preparation4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid. The product was isolated as a white solid (20 mg, 12.2%). LCMS:m/e 756.7 (MH⁺), 2.41 min (method 13). ¹H NMR (400 MHz, MeOD) δ ppm 7.95(m, J=8.3 Hz, 2H), 7.24 (m, J=8.3 Hz, 2H), 5.32 (d, J=4.8 Hz, 1H), 4.86(s, 1H), 4.73 (s, 1H), 4.19 (t, J=7.5 Hz, 2H), 4.02-4.14 (m, 6H), 3.88(t, J=4.4 Hz, 4H), 3.70-3.84 (m, 4H), 3.57 (br. s., 2H), 3.42-3.51 (m,2H), 2.96-3.19 (m, 4H), 2.79 (br. s., 1H), 2.01-2.26 (m, 5H), 1.87-1.96(m, 1H), 1.68-1.82 (m, 6H), 1.46-1.68 (m, 8H), 1.26-1.45 (m, 4H),1.17-1.26 (m, 4H), 1.13 (s, 3H), 1.05 (s, 3H), 0.99 (s, 3H), 0.97 (s,3H).

Example 161 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(thiazol-4-ylmethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 4-(chloromethyl)thiazole as the alkylating agent in Step 1.MS: m/e 627.5 (M+H)⁺, 1.56 min (method 12). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 0.95 (s., 3H) 0.96 (s, 3H) 1.01 (s, 3H) 1.10 (s, 3H)1.21 (s, 3H) 1.72 (s, 3H) 0.89-1.83 (m, 16H) 1.84-2.05 (m, 3H) 2.07-2.22(m, 1H) 2.13 (dd, J=17.07, 6.53 Hz, 1H) 2.22-2.32 (m, 1H) 2.33-2.49 (m,1H) 4.24 (d, J=14.05 Hz, 1H) 4.70 (s, 1H) 4.72 (d, J=13.55 Hz, 1H) 4.81(s, 1H) 5.31 (dd, J=6.02, 1.51 Hz, 1H) 7.24 (d, J=8.28 Hz, 2H) 7.59 (s,1H) 8.00 (d, J=8.28 Hz, 2H) 8.83 (s, 1H).

Example 162 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-methylthiazol-4-yl)methylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 4-(chloromethyl)-2-methylthiazole hydrochloride as thealkylating agent in Step 1. MS: m/e 641.5 (M+H)⁺, 1.56 min (method 12).¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96 (s, 3H) 0.97 (s, 3H) 1.02 (s,3H) 1.10 (s, 3H) 1.26 (s, 3H) 1.71 (s, 3H) 0.88-1.83 (m, 16H) 1.89-2.04(m, 3H) 2.08-2.21 (m, 1H) 2.14 (dd, J=17.19, 6.15 Hz, 1H) 2.22-2.30 (m,1H) 2.33-2.45 (m, 1H) 2.68 (s, 3H) 4.09 (d, J=13.05 Hz, 1H) 4.64 (d,J=12.80 Hz, 1H) 4.69 (s, 1H) 4.80 (s, 1H) 5.32 (d, J=4.52 Hz, 1H) 7.24(d, J=8.28 Hz, 2H) 7.28 (s, 1H) 8.00 (d, J=8.28 Hz, 2H).

Example 163 Preparation of4-((1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

A mixture of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (100 mg, 0.145 mmol) and 10% Pd/C (90 mg, 0.087 mmol) in methanol(5 mL) and ethyl acetate (5 mL) was loaded onto a PARR shaker reactorand treated with hydrogen for 25 hours under 40 psi at room temperature.The reaction mixture was filtered through a celite pad to remove thecatalyst. The filtrate was purified by HPLC to provide the titlecompound as a white solid (5.6 mg, 28%). LCMS: m/e 693.46 (M+H)⁺, 2.46min (method 10). ¹H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (d, J=8.2Hz, 2H), 7.31 (d, J=8.2 Hz, 2H), 5.39 (d, J=4.6 Hz, 1H), 3.50-3.36 (m,1H), 3.36-3.21 (m, 6H), 3.21-2.98 (m, 5H), 2.31-1.29 (m, 24H), 1.29 (s,3H), 1.13 (s, 6H), 1.03 (s, 3H), 1.01 (s, 3H), 0.94 (d, J=6.7 Hz, 3H),0.86 (d, J=6.7 Hz, 3H).

Example 164 Preparation ofN-(cyclopropylsulfonyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzamide

Step 1. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoylchloride

A mixture of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (200 mg, 0.289 mmol) and thionyl chloride (0.211 mL, 2.89 mmol) indichloroethane (5 mL) was refluxed for 30 h. The reaction mixture wasconcentrated under reduced pressure to provide the title compound as awhite solid (150 mg, 73%). LCMS: m/e 705.46 (M−Cl+OMe+H)⁺, 3.0 min(method 10).

Step 2. Preparation ofN-(cyclopropylsulfonyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzamide

A mixture of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoylchloride (30 mg, 0.042 mmol), cyclopropanesulfonamide (6.15 mg, 0.051mmol), Hunig's Base (0.022 mL, 0.127 mmol) and DMAP (2.58 mg, 0.021mmol) in dichloromethane (1 mL) was stirred for 16 h at roomtemperature. The crude reaction mixture was purified by prep HPLC toprovide the title compound as a white solid (4 mg, 11%). LCMS: m/e794.53 (M+H)⁺, 2.44 min (method 10). ¹H NMR (500 MHz, Acetic acid d4) δppm 7.94 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.2 Hz, 2H), 5.38 (d, J=4.6 Hz,1H), 4.84 (s, 1H), 4.74 (s, 1H), 3.56-3.39 (m, 1H), 3.38-3.21 (m, 7H),3.21-3.11 (m, 3H), 3.11-3.03 (m, 2H), 3.01-2.89 (m, 1H), 2.41-1.16 (m,26H), 1.76 (s, 3H), 1.29 (s, 3H), 1.15 (s, 3H), 1.11 (s, 3H), 1.03 (s,3H), 1.00 (s, 3H).

Example 165 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-morpholinopropylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 4-(3-chloropropyl)morpholine hydrochloride as the alkylatingreagent in Step 1. The product was isolated as a white solid (60 mg,48.1%). LCMS: m/e 657.55 (M+H)⁺, 2.24 min (method 13). ¹H NMR (400 MHz,METHANOL-d₄) δ 7.95 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 5.33 (d,J=4.5 Hz, 1H), 4.88 (s, 1H), 4.75 (s, 1H), 3.97 (m, 4H), 3.30-3.04 (m,8H), 2.85-2.66 (m, 1H), 2.46-2.24 (m, 2H), 2.24-1.85 (m, 7H), 1.82-1.65(m, 7H), 1.65-1.45 (m, 7H), 1.45-1.26 (m, 4H), 1.22 (s, 3H), 1.14 (s,3H), 1.08 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H)

Example 166 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((2-(pyridin-4-yl)ethyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 4-(2-chloroethyl)pyridine as the alkylating reagent inStep 1. The product was isolated as an off white solid (10 mg, 2.9%).LCMS: m/e 635.40 (M+H)⁺, 2.31 min (method 13). ¹H NMR (400 MHz,METHANOL-d₄) δ 8.83 (d, J=5.8 Hz, 2H), 8.06 (d, J=6.0 Hz, 2H), 7.95 (d,J=8.5 Hz, 2H), 7.25 (d, J=8.3 Hz, 2H), 5.33 (d, J=4.5 Hz, 1H), 4.90 (s,1H), 4.76 (s, 1H), 3.57-3.46 (m, 4H), 2.86-2.75 (m, 1H), 2.27-2.08 (m,5H), 2.05-1.89 (m, 2H), 1.79 (s, 3H), 1.85-1.67 (m, 4H), 1.66-1.49 (m,7H), 1.45-1.23 (m, 4H), 1.21 (s, 3H), 1.14 (s, 3H), 1.09 (s, 3H), 1.00(s, 3H), 0.98 (s, 3H).

Example 167 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(bis(2-(pyrrolidin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 1-(2-chloroethyl)pyrrolidine hydrochloride as the alkylatingreagent in Step 1. The product was isolated as a white solid (10 mg,2.57%). LCMS: m/e 724.52 (M+H)⁺, 1.43 min (method 15). ¹H NMR (400 MHz,METHANOL-d) δ 7.88 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 5.26 (d,J=4.8 Hz, 1H), 4.79 (s, 1H), 4.66 (s, 1H), 4.03-3.86 (m, 4H), 3.86-3.62(m, 6H), 3.59-3.29 (m, 6H), 2.81-2.58 (m, 1H), 2.26 (br. s., 4H),2.21-1.88 (m, 9H), 1.82 (d, J=13.1 Hz, 1H), 1.73-1.62 (m, 5H), 1.62-1.40(m, 9H), 1.40-1.19 (m, 4H), 1.13 (s, 4H), 1.06 (s, 3H), 1.01 (s, 3H),0.93 (s, 3H), 0.91 (s, 3H),

Example 168 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-thiomorpholinoethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 4-(2-chloroethyl)thiomorpholine hydrochloride (prepared asdescribe in WO 2009058859) as the alkylating reagent in Step 1. Theproduct was isolated as a white solid (3 mg, 0.85%). LCMS: m/e 659.37(M+H)⁺, 2.38 min (method 13). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.00 (d,J=8.3 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 5.32-5.19 (m, 1H), 4.77 (s, 1H),4.65 (s, 1H), 3.11-2.98 (m, 1H), 2.89 (m, 5H), 2.75 (m, 5H), 2.67-2.57(m, 1H), 2.31-2.16 (m, 1H), 2.14-1.85 (m, 6H), 1.71 (s, 7H), 1.59-1.40(m, 6H), 1.38-1.15 (m, 8H), 1.08-0.96 (m, 10H), 0.94 (s, 3H)

Example 169 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 3-chloro-N,N-dimethylpropan-1-amine hydrochloride as thealkylating reagent in Step 1. The product was isolated as a white solid(3 mg, 0.85%). LCMS: m/e 615.75 (M+H)⁺, 2.24 min (method 13). ¹H NMR(400 MHz, METHANOL-d₄) δ 7.95 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H),5.34 (s, 1H), 4.89 (s, 1H), 4.75 (s, 1H), 3.58-3.36 (m, 2H), 3.26 (br.s., 8H), 2.78 (d, J=7.5 Hz, 1H), 2.51-2.26 (m, 3H), 2.26-1.97 (m, 7H),1.92 (m, 1H), 1.78 (m, 6H), 1.63-1.47 (m, 6H), 1.45-1.36 (m, 2H),1.32-1.18 (m, 5H), 1.14 (s, 3H), 1.08 (s, 3H), 1.00 (s, 3H), 0.98 (s,3H)

Example 170 Preparation of1-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-carboxyphenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)amino)ethyl)piperidine-4-carboxylicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using methyl 1-(2-chloroethyl)piperidine-4-carboxylatehydrochloride (prepared as described below) as the alkylating reagent inStep 1. The product was isolated as a white solid (8 mg, 83%). LCMS: m/e685.6 (M+H)⁺, 2.33 min (method 10). ¹H NMR (400 MHz, METHANOL-d₄) δ 7.94(d, J=8.3 Hz, 2H), 7.23 (d, J=8.3 Hz, 2H), 5.31 (d, J=4.5 Hz, 1H), 4.86(s, 1H), 4.74 (s, 1H), 3.48-3.36 (m, 5H), 3.12-2.88 (m, 2H), 2.79-2.69(m 1H), 2.68-2.60 (m, 1H), 2.24-2.11 (m, 4H), 2.11-2.00 (m, 4H),1.97-1.81 (m, 3H), 1.77 (s, 3H), 1.81-1.71 (m, 2H), 1.70-1.46 (m, 10H),1.45-1.27 (m, 4H), 1.21 (s, 3H), 1.12 (s, 3H), 1.06 (s, 3H), 0.98 (s,3H), 0.97 (s, 3H).

Preparation of methyl 1-(2-chloroethyl)piperidine-4-carboxylate

To a solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (5.4g, 22.19 mmol) in ether was added hydrogen chloride (27.7 mL, 111 mmol)in dioxane. The resulted clear solution was stirred for 4 hours. Bubblesand white precipitates were observed. Then the solvent was removed anddried in vacuo. The residue was suspended in acetonitrile (50 mL), and2-bromoethanol (1.567 mL, 22.19 mmol) was added followed by powderedK₂CO₃ (14.72 g, 107 mmol). After the reaction mixture was refluxed for18 hours, it was filtered and concentrated. The residue was redissolvedin water (50.0 mL) and extracted with ethyl acetate (50.0 mL). Theorganic layer was dried over sodium sulfate. After filtration thesolvent was removed in vacuo. The residue was dissolved in DCE (50.0 mL)before sulfurous dichloride (2.428 mL, 33.3 mmol) was added. Thereaction mixture was reflux for 3 hours, then all volatile was removedin vacuo, the resulting solid was suspended in ether, then filtered andwashed with ether (50.0 mL), resuspended in ethyl acetate andneutralized with sodium bicarbonate. The organic layer was collected anddried with sodium sulfate to afford methyl1-(2-chloroethyl)piperidine-4-carboxylate (1 g, 4.86 mmol, 21.91% yield)as a brown oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ 3.70 (s, 3H), 3.61 (t,J=7.0 Hz, 2H), 2.97-2.86 (m, 2H), 2.75 (t, J=7.2 Hz, 2H), 2.40-2.27 (m,1H), 2.19 (m, 2H), 2.01-1.88 (m, 2H), 1.87-1.72 (m, 2H).

Example 171 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(4-(dimethylcarbamoyl)piperidin-1-yl)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. To a solution of methyl1-(2-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-ylamino)ethyl)piperidine-4-carboxylate(40 mg) in dioxane (1 mL) was added lithium hydroxide (2.7 mg, 0.112mmol) in water (1 mL). A white precipitate was observed. The mixture wasstirred at 25° C. for 3 hours. The desired product was observed at m/e699.7 (M+H)⁺, 2.703 min, method 10. The reaction mixture was neutralizedwith 1 N HCl to pH˜4 and diluted with methlylene chloride (10 mL). Theorganic layer was then collected, dried over sodium sulfate andfiltered. After removal of solvent, the crude product was obtained as anoil (40 mg, ˜100%) which was used without further purification.

Step 2. To a solution of1-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)amino)ethyl)piperidine-4-carboxylicacid (40 mg, 0.057 mmol) in CH₂Cl₂ (5 ml) at rt was added dimethylamine(7.6 mg, 0.17 mmol) and HATU (65 mg, 0.18 mmol) followed by DIEA (29 mg,0.23 mmol). The mixture was stirred for 3 hour at rt. The resultedmixture was diluted with ethyl acetate and washed with water. Theorganic layer was dried over sodium sulfate. The crude product wasobtained after removal of solvent as a white solid (40 mg, ˜100%) whichwas used without further purification

Step 3.4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(4-(dimethylcarbamoyl)piperidin-1-yl)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid was prepared following step 2 of the method described above for thesynthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid. The product was isolated as a white solid (9 mg, 23.0%). LCMS: m/e712.64 (M+H)⁺, 2.265 min (method 11). ¹H NMR (400 MHz, METHANOL-d₄) δ7.95 (d, J=8.3 Hz, 2H), 7.25 (d, J=8.3 Hz, 2H), 5.33 (d, J=4.5 Hz, 1H),4.87 (s, 1H), 4.74 (s, 1H), 3.65-3.38 (m, 6H), 3.16 (s, 3H), 3.05 (m,2H), 2.96 (s, 3H), 2.75 (m, 1H), 2.23-1.85 (m, 11H), 1.82-1.74 (m, 6H),1.70-1.48 (m, 9H), 1.44-1.28 (m, 3H), 1.22 (m, 4H), 1.13 (s, 3H), 1.08(s, 3H), 1.00 (s, 3H), 0.98 (s, 3H),

Example 172 Preparation of4-(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(4,4-difluoropiperidin-1-yl)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 4,4-difluoropiperidine hydrochloride as the alkylatingreagent in Step 3. The product was isolated as a white solid (20 mg,58.3%). LCMS: m/e 677.57 (M+H)⁺, 2.30 min (method 11). ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.97 (d, J=8.3 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H), 5.27 (d,J=4.8 Hz, 1H), 4.82 (s, 1H), 4.70 (s, 1H), 3.32 (m, 1H), 3.19-3.05 (m,1H), 2.94 (m, 2H), 2.83-2.68 (m, 5H), 2.36-2.21 (m, 2H), 2.15-1.90 (m,7H), 1.74 (br. s., 7H), 1.60-1.45 (m, 6H), 1.44-1.30 (m, 4H), 1.26 (s,2H), 1.18 (s, 3H), 1.06 (s, 4H) 0.98 (s, 3H), 0.97 (s, 3H), 0.95 (s,3H). ¹⁹F NMR (376 MHz, CHLOROFORM-d) δ −98.39 (br. s., 2F)

Example 173 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate.To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.160 g, 0.276 mmol) in a mixture of acetonitrile (25 mL) anddichloroethane (5 mL) was added anhydrous potassium phosphate (0.25 gm,1.18 mmol). The resulting suspension was heated to 120° C. undernitrogen in a thick-walled tube for 24 hours. The cooled reactionsuspension was filtered through a short bed of silica gel (Type-H),washed with ethyl acetate (60 mL). The clear filtrate was concentratedin vacuo to give a white solid (0.150 g, 96%). LCMS: m/e 570.5 (M+H)⁺,3.32 min (method 12, but modified to gradient over 3 minutes). ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.95 (d, J=8.3 Hz, 2H), 7.22 (d, J=8.5 Hz,2H), 5.31 (dd, J=6.1, 1.6 Hz, 1H), 4.81-4.73 (m, 1H), 4.67-4.59 (m, 1H),3.93 (s, 3H), 2.82-2.45 (m, 1H), 2.19-2.04 (m, 1H), 1.88-1.74 (m, 1H),1.71 (s, 3H), 1.68 (br. s., 1H), 1.63-1.21 (m, 7H), 1.11 (s, 3H), 1.01(s, 3H), 1.00 (s, 3H), 0.95 (s, 6H).

Step 2. To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.150 g, 0.264 mmol) in a mixture of methanol (2 mL) and THF (6 mL) atrt was added a stock solution of lithium hydroxide (1.0 Molar, 2 mL, 2.0mmol) forming a thick suspension. The mixture was kept at 50° C. undernitrogen for 60 hours. The reaction mixture was neutralized with HCl(0.5 Molar, 10 mL), the organic material was extracted into ethylacetate (30 mL). While the 2-phase mixture was stirred at rt, a whiteprecipitate slowly separated out. It was filtered to give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid as a white solid (99 mg, 68%). LCMS: m/e 592.5 (M+MeOH+Na)⁺, 3.03min (method 12, but modified to gradient over 3 minutes). Selected ¹HNMR (400 MHz, CHLOROFORM-d) δ 8.01 (d, J=8.3 Hz, 2H), 7.24 (d, J=8.3 Hz,2H), 5.28 (m, 1H), 4.94 (br. s, 1H), 4.73 (br. s, 1H), 1.74 (s, 3H),1.20 (s, 3H), 1.09 (s, 3H), 1.01 (s, 3H), 0.99 (s, 3H), 0.97 (s, 3H).

Example 174 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1-(tert-butoxycarbonyl)piperidin-3-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of tert-butyl3-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-ylamino)methyl)piperidine-1-carboxylate.To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(30 mg, 0.055 mmol) in dichloroethane (0.5 mL) was added3-formyl-piperidine-1-carboxylic acid tert-butyl ester (14.71 mg, 0.069mmol) and titanium (IV) isopropoxide (0.020 mL, 0.069 mmol). The mixturewas stirred at rt for 1 h and sodium triacetoxyborohydride (23.38 mg,0.110 mmol) was added. The mixture was stirred at rt for 16.5 h, thenwas diluted with 3 mL of sat. NaHCO₃ and was extracted withdichloromethane (3×5 mL). The combined organic layers were dried withNa₂SO₄, were filtered and were concentrated under reduced pressure. Theresidue was adsorbed to silica gel and was purified by flashchromatography using a 0-10% ethyl acetate in hexanes gradient and aThomson 12 g silica gel column. The fractions containing the expectedproduct were combined and concentrated under reduced pressure to givethe title compound as an off-white foam. LCMS: m/e 741.7 (M+H)⁺, 3.76min (method 2).

Step 2. To a solution of tert-butyl3-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-ylamino)methyl)piperidine-1-carboxylate(0.029 g, 0.039 mmol) in 1,4-dioxane (2 mL) was added NaOH (1N) (0.196mL, 0.196 mmol). The mixture was heated to 85° C. for 22 h, then wascooled to rt, was diluted with MeOH, and was purified by prep HPLC. Thefractions containing the expected product were combined and concentratedunder reduced pressure to give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1-(tert-butoxycarbonyl)piperidin-3-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (24 mg, 0.031 mmol, 56% yield over 2 steps) as a clear, colorlessfilm. LCMS: m/e 727.7 (M+H)⁺, 2.00 min (method 2). ¹H NMR (500 MHz,Chloroform-d) δ ppm 7.98 (d, J=7.93 Hz, 2H), 7.21 (d, J=7.93 Hz, 2H),5.29 (d, J=5.49 Hz, 1H), 4.70 (br. s., 1H), 4.58 (br. s., 1H), 3.82-4.51(m, 5H), 1.68 (s, 3H), 1.47 (d, J=4.58 Hz, 9H), 1.10 (d, J=7.93 Hz, 3H),0.98 (br. s., 6H), 0.93 (s, 3H), 0.92 (s, 3H), 0.90-2.85 (m, 30H).

Example 175 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(piperidin-3-ylmethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a solution of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1-(tert-butoxycarbonyl)piperidin-3-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (0.019 g, 0.026 mmol) in dichloromethane (1 mL) was added TFA (0.25mL, 3.24 mmol). The mixture was stirred at rt for 1.75 h then wasconcentrated under reduced pressure. The residue was purified by prepHPLC. The fractions containing the expected product were combined andwere concentrated under reduced pressure to give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(piperidin-3-ylmethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (14.2 mg, 0.021 mmol, 81% yield) as a white solid. LCMS: m/e 627.6(M+H)⁺, 1.50 min (method 2).

Examples 176 and 177 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(methylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid and4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(dimethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. To a sealable vial containing methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,HCl (1.0 g, 1.72 mmol) was added potassium carbonate (0.48 g, 3.45mmol). The mixture was diluted with DMF (15 mL) and methyl iodide (323mL, 3.45 mmol) was added. The vial was sealed and the mixture was heatedto 75° C. for 4 h then was cooled to rt. The vial was opened to the airand was stirred at rt overnight. The mixture was diluted with 20 mL ofsaturated aqueous sodium thiosulfate. Solids formed and were collectedby filtration and were washed with water. The residue was purified byflash chromatography in silica gel using a 0-25% ethyl acetate inhexanes gradient with 0.1% ammonium hydroxide added to the mixture. Twomain isolates were recovered from the column. The less polar product,methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(dimethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.247 g, 0.405 mmol, 23.5% yield) was recovered as a white foam. Themore polar isolate, methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(methylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.5 g, 0.807 mmol, 46.8% yield), was recovered as a white solid. LCMSof the less polar isolate: m/e 572.6 (M+H)⁺, 2.03 min (method 2). ¹H NMR(400 MHz, Chloroform-d) δ=7.96-7.92 (m, 2H), 7.23-7.19 (m, 2H),5.31-5.29 (m, 1H), 4.71 (d, J=2.0 Hz, 1H), 4.61 (dd, J=2.3, 1.3 Hz, 1H),3.92 (s, 3H), 2.86 (td, J=11.2, 6.1 Hz, 1H), 2.34-2.24 (m, 7H), 2.12(dd, J=17.1, 6.5 Hz, 1H), 2.04-1.80 (m, 5H), 1.70 (s, 3H), 1.10 (s, 3H),1.02 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H), 0.94 (s, 3H), 1.74-0.85 (m,15H). LCMS of the more polar isolate: m/e 558.6 (M+H)⁺, 2.04 min (method2). ¹H NMR (400 MHz, Chloroform-d)=7.93 (d, J=8.0 Hz, 2H), 7.20 (d,J=8.3 Hz, 2H), 5.30 (dd, J=6.1, 1.6 Hz, 1H), 4.72 (d, J=2.0 Hz, 1H),4.59 (s, 1H), 3.92 (s, 3H), 2.60 (td, J=10.9, 5.8 Hz, 1H), 2.24 (s, 3H),2.11 (dd, J=17.2, 6.1 Hz, 1H), 2.03-1.91 (m, 2H), 1.88-1.79 (m, 2H),1.09 (s, 3H), 1.00 (s, 3H), 0.99 (s, 3H), 0.94 (s, 3H), 0.93 (s, 3H),1.69-0.91 (m, 20H).

Step 2. The Saponification of the Isolates were Carried OutIndependently:

Example 176 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(methylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, HCl

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(methylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(88 mg, 0.158 mmol) in 1,4-dioxane (3 mL) was added NaOH (1M) (1 mL,1.000 mmol). The mixture was heated to 75° C. for 17 h then was cooledto rt and was acidified with 3 mL of 1N HCl. Solids formed upon standingand were collected by filtration and were washed with water. The solidswere dissolved and were purified by flash chromatography using a 0-40%methanol in ethyl acetate gradient and a Thomson 25 g silica gel column.The fractions containing the expected product were combined and wereconcentrated under reduced pressure then were redissolved indichloromethane and methanol and were filtered through a plug of celite.The filtrate was concentrated under reduced pressure to give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(methylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, HCl (40 mg, 0.065 mmol, 41% yield) as a white solid. LCMS: m/e544.5 (M+H)⁺, 1.79 min (method 2). ¹H NMR (500 MHz, Acetic acid d₄)δ=8.01 (d, J=8.2 Hz, 2H), 7.27 (d, J=8.2 Hz, 2H), 5.34 (d, J=4.6 Hz,1H), 4.84 (s, 1H), 4.71 (s, 1H), 2.85-2.77 (m, 1H), 2.74 (s, 3H), 1.75(s, 3H), 1.16 (s, 3H), 1.10 (s, 3H), 1.06 (s, 3H), 0.99 (s, 3H), 0.97(s, 3H), 2.24-0.95 (m, 22H).

Example 177 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(dimethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a suspension of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(dimethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,HCl (100 mg, 0.164 mmol) in 1,4-dioxane (3 mL) was added 1N NaOH (1 mL,1.000 mmol) and the mixture was heated to 70° C. After 3.75 h themixture was cooled to rt and was diluted with 2 mL of MeOH and then 1NHCl (6 mL) was added. The solids that formed were collected byfiltration and were washed with water. The solids were dissolved indioxane and methanol and were purified by prep HPLC. The fractionscontaining the expected product were combined and concentrated underreduced pressure to give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(dimethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (45 mg, 0.077 mmol, 46.6% yield) as a white solid. LCMS: m/e 558.3(M+H)⁺, 2.28 min (method 11). ¹H NMR (500 MHz, Acetic acid d₄) δ ppm8.04 (2H, d, J=8.2 Hz), 7.30 (2H, d, J=8.2 Hz), 5.37 (1H, d, J=4.9 Hz),4.92 (1H, s), 4.77 (1H, s), 3.08 (7H, br. s.), 1.80 (3H, s), 1.22 (3H,s), 1.18 (3H, s), 1.09 (3H, s), 1.02 (3H, s), 1.00 (3H, s), 0.98-2.46(22H, m).

Example 178 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(acetyl(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(acetyl(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate.To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((1,1-dioxido-4-thiomorpholinyl)acetyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.05 g, 0.071 mmol) in dichloroethane (1 mL) and Hunig's base (0.062mL, 0.355 mmol) was added acetyl chloride (0.020 mL, 0.284 mmol). Themixture was heated to 50° C. After heating the mixture for 71.25 h, themixture was cooled to rt and was directly loaded onto a 12 g Thomsonsilica gel column and was purified by Biotage flash chromatography usinga 0-5% MeOH in dichloromethane gradient. The fractions containing theexpected product were combined and were concentrated under reducedpressure to give methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(acetyl(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(40 mg, 0.054 mmol, 75%) as a clear, colorless film. LCMS: m/e 747.5(M+H)⁺, 2.26 min (method 2).

Step 2. To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(acetyl(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(40 mg, 0.054 mmol) in 1,4-dioxane (1 mL) was added NaOH (1N) (0.27 mL,0.27 mmol). The mixture was stirred at rt for 16.5 h then was purifieddirectly by prep HPLC. The fractions containing the expected productwere combined and concentrated under reduced pressure to give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(acetyl(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (14 mg, 0.018 mmol, 33%) as a white solid. LCMS: m/e 733.5 (M+H)⁺,1.96 min (method 2). ¹H NMR (400 MHz, Chloroform-d) δ=7.99 (d, J=7.8 Hz,2H), 7.22 (d, J=7.8 Hz, 2H), 5.23 (d, J=4.0 Hz, 1H), 4.85 (br. s., 1H),4.68 (br. s., 1H), 3.65 (br. s., 2H), 3.40-3.04 (m, 8H), 2.97-2.46 (m,4H), 1.74 (s, 3H), 1.27 (s, 3H), 1.03-0.98 (m, 9H), 0.95 (br. s., 3H),0.89 (br. s., 3H), 2.20-0.71 (m, 21H).

Example 179 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoroethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoroethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate.To a sealable vial containing methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,HCl (0.075 g, 0.129 mmol) was added potassium carbonate (0.036 g, 0.258mmol). The mixture was diluted with DMF (1 mL) and 1-fluoro-2-iodoethane(0.032 ml, 0.388 mmol) was added. The vial was sealed and the mixturewas heated to 75° C. for 26 h then was cooled to rt. The mixture wasdiluted with 3 mL of sat. aq. sodium thiosulfate and was extracted withdichloromethane (3×4 mL). The combined organic layers were dried withsodium sulfate, the drying agent was removed by filtration and thefiltrate was concentrated under reduced pressure. The residue wasdissolved in toluene and was loaded onto a Thomson 12 g silica gelcolumn and was purified by Biotage flash chromatography using a 0-15%ethyl acetate in hexanes gradient with 0.1% ammonium hydroxide added tothe mixture. The fractions containing the expected product were combinedand concentrated under reduced pressure to give methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoroethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.062 g, 0.103 mmol, 80% yield) as a white foam. LCMS: m/e 590.6(M+H)⁺, 2.05 min (method 2). ¹H NMR (400 MHz, chloroform-d) 7.94 (d,J=8.53 Hz, 2H), 7.21 (d, J=8.28 Hz, 2H), 5.30 (dd, J=2.01, 6.27 Hz, 1H),4.73 (d, J=2.01 Hz, 1H), 4.58-4.64 (m, 2H), 4.50 (t, J=4.89 Hz, 1H),3.92 (s, 3H), 2.57-2.85 (m, 3H), 2.11 (dd, J=6.40, 17.19 Hz, 1H), 1.71(s, 3H), 1.10 (s, 3H), 1.00 (s, 3H), 0.99 (s, 3H), 0.94 (s, 3H), 0.94(s, 3H), 0.86-2.05 (m, 21H).

Step 2. To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoroethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.059 g, 0.100 mmol) in 1,4-dioxane (2 mL) was added NaOH (1N) (0.5 mL,0.500 mmol). The mixture was heated to 85° C. for 15.25 h, was cooled tort, then was diluted with methanol and 1,4-dioxane and was purified byprep HPLC. The fractions containing the expected product were combinedand concentrated under reduced pressure to give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoroethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (29.2 mg, 0.048 mmol, 48.2% yield) as a white solid. LCMS: m/e576.6 (M+H)⁺, 1.74 min (method 2). ¹H NMR (400 MHz, Acetic acid d₄) δ7.99 (d, J=8.53 Hz, 2H), 7.26 (d, J=8.28 Hz, 2H), 5.33 (d, J=4.77 Hz,1H), 4.73-4.99 (m, 3H), 4.70 (s, 1H), 3.41-3.73 (m, 2H), 2.83-2.94 (m,1H), 1.73 (s, 3H), 1.19 (s, 3H), 1.11 (s, 3H), 1.05 (s, 3H), 0.98 (s,3H), 0.96 (s, 3H), 0.82-2.27 (m, 22H).

Example 180 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate.To a sealable vial containing methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,HCl (0.075 g, 0.129 mmol) was added potassium carbonate (0.036 g, 0.258mmol). The mixture was diluted with DMF (1 mL) and iodoethane (0.031 mL,0.388 mmol) was added. The mixture was heated to 75° C. for 23 h thenwas cooled to rt. The mixture was diluted with 1 mL of DMF andadditional iodoethane (0.031 mL, 0.388 mmol) was added to the mixture.The vial was sealed and heated to 75° C. for 24 h, then was concentratedunder reduced pressure and was adsorbed to silica gel. The mixture waspurified by flash chromatography using a 0-25% EtOAc in hexanes gradientwith 0.1% ammonium hydroxide added and a Thomson 12 g silica gel column.The fractions containing the expected product were combined and wereconcentrated under reduced pressure to give methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.039 g, 0.065 mmol, 50.1% yield) as a white foam. LCMS: m/e 572.7(M+H)⁺, 2.16 min (method 2). ¹H NMR (400 MHz, chloroform-d) δ 7.94 (d,J=8.28 Hz, 2H), 7.21 (d, J=8.53 Hz, 2H), 5.30 (dd, J=1.76, 6.27 Hz, 1H),4.73 (d, J=2.51 Hz, 1H), 4.59 (dd, J=1.38, 2.38 Hz, 1H), 3.92 (s, 3H),2.62 (dt, J=5.40, 10.98 Hz, 1H), 2.38-2.53 (m, 2H), 2.11 (dd, J=6.40,17.19 Hz, 1H), 1.88-2.03 (m, 3H), 1.83 (dd, J=7.78, 12.55 Hz, 1H), 1.70(s, 3H), 1.10 (s, 3H), 1.11 (t, J=7.03 Hz, 3H), 0.99 (s, 6H), 0.94 (s,3H), 0.94 (s, 3H), 0.91-1.74 (m, 17H).

Step 2. To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.037 g, 0.065 mmol) in 1,4-dioxane (1.5 mL) was added NaOH (1N) (0.3mL, 0.300 mmol). The mixture was heated to 75° C. for 18.5 h then wascooled to rt, was diluted with methanol and 1,4-dioxane, was filteredthrough a plug of glass wool and was purified by prep HPLC. Thefractions containing the expected product were combined and wereconcentrated under reduced pressure to give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (0.023 g, 0.040 mmol, 61.2% yield) as a white solid. LCMS: m/e558.6 (M+H)⁺, 1.77 min (method 2). ¹H NMR (400 MHz, Acetic acid d₄) δ7.99 (d, J=8.53 Hz, 2H), 7.26 (d, J=8.28 Hz, 2H), 5.33 (d, J=4.52 Hz,1H), 4.82 (s, 1H), 4.69 (s, 1H), 3.23 (q, J=7.11 Hz, 2H), 2.81-2.92 (m,1H), 1.72 (s, 3H), 1.40 (t, J=7.15 Hz, 3H), 1.19 (s, 3H), 1.09 (s, 3H),1.05 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H), 0.83-2.24 (m, 22H).

Example 181 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(isobutylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(isobutylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate.To a sealable vial containing methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,HCl (0.075 g, 0.129 mmol) was added potassium carbonate (0.036 g, 0.258mmol). The mixture was diluted with DMF (1 mL) and isobutyl iodide(0.045 mL, 0.388 mmol) was added. The vial was sealed and the mixturewas heated to 75° C. for 23 h, then the mixture was cooled to rt. LC/MSshowed formation of the expected product, but starting material stillremained. To the mixture was added additional isobutyl iodide (0.045 mL,0.388 mmol) and the vial was sealed and heated to 75° C. for 48 h. Themixture was cooled to rt then was diluted with 5 mL of water. The solidsthat formed were collected by filtration then were washed with water togive the expected product, methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(isobutylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(53 mg, 0.075 mmol, 58.1% yield) as a light-yellow solid. The crudeproduct was used in the next step with no additional purification. LCMS:m/e 600.6 (M+H)⁺, 2.14 min (method 2).

Step 2. To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(isobutylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(52 mg, 0.087 mmol) in 1,4-dioxane (1.5 mL) was added NaOH (1N) (0.3 mL,0.300 mmol). The mixture was heated to 75° C. for 67 h then was cooledto rt. The mixture was diluted with 1,4-dioxane and methanol, wasfiltered through a plug of glass wool, and was purified by prep HPLC.The fractions containing the expected product were combined andconcentrated under reduced pressure to give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(isobutylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (25.2 mg, 0.041 mmol, 47.1% yield) as a white solid. LCMS: m/e586.6 (M+H)⁺, 1.85 min (method 2). ¹H NMR (400 MHz, Acetic acid d₄) δ8.00 (d, J=8.28 Hz, 2H), 7.26 (d, J=8.28 Hz, 2H), 5.33 (d, J=4.52 Hz,1H), 4.81 (s, 1H), 4.69 (s, 1H), 3.15 (dd, J=5.02, 12.05 Hz, 1H),2.88-2.98 (m, 1H), 2.78 (dd, J=9.03, 11.80 Hz, 1H), 1.72 (s, 3H), 1.22(s, 3H), 1.10 (s, 3H), 1.09 (d, J=6.78 Hz, 3H), 1.06 (s, 3H), 1.01 (d,J=6.78 Hz, 3H), 0.98 (s, 3H), 0.96 (s, 3H), 0.83-2.31 (m, 23H).

Example 182 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((3,3,3-trifluoropropyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((3,3,3-trifluoropropyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a sealable vial containing methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,HCl (0.075 g, 0.129 mmol) was added potassium carbonate (0.036 g, 0.258mmol). The mixture was diluted with DMF (1 mL) and1-iodo-3,3,3-trifluoropropane (0.045 mL, 0.388 mmol) was added. The vialwas sealed and the mixture was heated to 75° C. for 23 h then was cooledto rt. LC/MS showed a mixture of starting material and product. Anadditional 0.045 mL of 1-Iodo-3,3,3-trifluoropropane was added and themixture and was heated to 75° C. for 48 h then was cooled to rt. LC/MSshowed further progression, but the reaction was still not complete. Anadditional 0.045 mL of 1-iodo-3,3,3-trifluoropropane was added and themixture was heated to 75° C. for 71 h, then was cooled to rt and wasconcentrated under reduced pressure. The mixture was adsorbed to silicagel and was purified by flash chromatography using a 0-15% EtOAc inhexanes gradient with 0.1% ammonium hydroxide added to the mixture and aThomson 12 g silica gel column. The fractions containing the expectedproduct were combined and were concentrated under reduced pressure togive methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((3,3,3-trifluoropropyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.032 g, 0.044 mmol, 34.1% yield) as a white foam. LCMS: m/e 640.6(M+H)⁺, 2.15 min (method 2). ¹H NMR (500 MHz, chloroform-d) δ 7.92 (d,J=8.24 Hz, 2H), 7.19 (d, J=8.24 Hz, 2H), 5.28 (dd, J=1.53, 6.10 Hz, 1H),4.70 (d, J=1.83 Hz, 1H), 4.59 (s, 1H), 3.90 (s, 3H), 2.60-2.73 (m, 2H),2.56 (dt, J=5.34, 10.91 Hz, 1H), 2.21-2.32 (m, 2H), 2.09 (dd, J=6.41,17.09 Hz, 1H), 1.68 (s, 3H), 1.07 (s, 3H), 0.98 (s, 6H), 0.92 (s, 3H),0.92 (br. s., 3H), 0.84-2.01 (m, 21H).

Step 2. To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((3,3,3-trifluoropropyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.032 g, 0.050 mmol) in 1,4-dioxane (1 mL) was added NaOH (1N) (0.2 mL,0.200 mmol). The mixture was heated to 75° C. for 22.5 h then was cooledto rt. The mixture was diluted with methanol, was filtered through aplug of glass wool and was purified by Prep HPLC. The fractionscontaining the expected product were combined and concentrated underreduced pressure to give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((3,3,3-trifluoropropyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (0.022 g, 0.033 mmol, 66.8% yield) as a white solid. LCMS: m/e626.6 (M+H)⁺, 1.87 min (method 2). ¹H NMR (400 MHz, Acetic acid d₄)δ7.99 (d, J=8.28 Hz, 2H), 7.25 (d, J=8.28 Hz, 2H), 5.33 (d, J=4.77 Hz,1H), 4.82 (s, 1H), 4.70 (s, 1H), 3.36-3.51 (m, 2H), 2.81-2.97 (m, 3H),2.12-2.28 (m, 4H), 1.72 (s, 3H), 1.17 (s, 3H), 1.09 (s, 3H), 1.05 (s,3H), 0.98 (s, 3H), 0.96 (s, 3H), 0.82-2.11 (m, 18H).

Example 183 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4,5-dimethylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(((9H-fluoren-9-yl)methoxy)carbonyl)thioureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate,HCl (2 g, 3.45 mmol) in DCM (50 mL) was added N,N-diisopropylethylamine(3.00 mL, 17.23 mmol) and Fmoc-isothioisocyanate (1.939 g, 6.89 mmol).The reaction mixture was stirred at rt. After 3 h, the reaction waswashed with 0.1 N HCl (50 mL). The aqueous layer was extracted with DCM(50 mL). The combined organic layer was washed with brine, dried overMgSO₄, filtered and concentrated to about 30 mL of DCM and treated withMeOH (100 mL). The mixture was concentrated to remove all DCM untilapproximately 50 mL of MeOH remained. The resulting yellow precipitatewas filtered and washed with MeOH. The solid product was saved and theliquid filtrate was concentrated to effect more precipitation. Theresulting solid was isolated by filtration and washed with MeOH. Thecombined solid product was dried in a 50° C. vacuum oven to give methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(((9H-fluoren-9-yl)methoxy)carbonyl)thioureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(2.52 g, 3.05 mmol, 89% yield) as a yellow solid. ¹H NMR (500 MHz,CHLOROFORM-d) δ 9.84 (s, 1H), 8.00 (s, 1H), 7.95 (d, J=8.2 Hz, 2H), 7.82(d, J=7.6 Hz, 2H), 7.64 (t, J=8.2 Hz, 2H), 7.49-7.44 (m, 2H), 7.38 (tt,J=1.5, 7.4 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 5.33-5.27 (m, 1H), 4.79 (s,1H), 4.67 (s, 1H), 4.58-4.53 (m, 2H), 4.29 (t, J=6.9 Hz, 1H), 3.93 (s,3H), 3.39 (d, J=13.7 Hz, 1H), 3.23 (dd, J=8.2, 12.8 Hz, 1H), 2.50 (dt,J=5.3, 10.8 Hz, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.98-1.88 (m, 1H),1.87-1.77 (m, 3H), 1.74 (s, 3H), 1.70 (d, J=17.4 Hz, 1H), 1.54-1.42 (m,8H), 1.41-1.29 (m, 3H), 1.24 (d, J=10.4 Hz, 1H), 1.19-1.10 (m, 2H), 1.05(s, 3H), 1.00 (s, 6H), 0.94 (s, 6H).

Step 2. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-thioureido-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(((9H-fluoren-9-yl)methoxy)carbonyl)thioureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(2.51 g, 3.04 mmol) in DCM (30 mL) was added piperidine (1.502 mL, 15.21mmol). The resulting brown reaction mixture was stirred at rt for 5 h.The reaction was concentrated and triturated with MeOH to give whitesolid product and fulvene adduct. This material was then re-dissolved inhot DCM and allowed to cool to rt. The resulting white precipitate wasfiltered and washed with cold DCM. The liquid filtrate was concentratedand more white precipitate was filtered. The combined white solidproduct was dried in a vacuum oven. The liquid filtrate was concentratedand loaded onto a column of SiO₂ (90 g) and eluted with DCM (1 L) toremove top spot by-product then the desired product was eluted with 97:3DCM:MeOH. After drying in a vacuum oven all solid product was combinedto give methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-thioureido-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(1.7 g, 2.82 mmol, 93% yield) as a white solid. LCMS: m/e 603.5 (M+H)⁺,2.51 min (method 1). ¹H NMR (500 MHz, CHLOROFORM-d) δ 7.94 (d, J=7.9 Hz,2H), 7.28 (s, 1H), 7.21 (d, J=7.9 Hz, 2H), 6.07 (br. s., 1H), 5.94 (br.s., 1H), 5.34-5.28 (m, 2H), 4.78 (s, 1H), 4.68 (br. s., 1H), 3.92 (s,3H), 2.64-2.55 (m, 1H), 2.17-2.02 (m, 2H), 1.85-1.74 (m, 3H), 1.71 (s,3H), 1.67 (br. s., 1H), 1.60-1.38 (m, 10H), 1.35-1.35 (m, 1H), 1.27-1.17(m, 2H), 1.13 (s, 4H), 1.02 (s, 3H), 1.00 (s, 3H), 0.95 (br. s., 3H),0.94 (br. s., 3H), 0.91-0.90 (m, 1H). ¹³C NMR (126 MHz, CHLOROFORM-d) δ182.0, 167.4, 148.8, 148.4, 146.4, 130.2, 128.6, 128.0, 124.0, 111.0,66.8, 53.5, 53.0, 52.1, 50.3, 49.5, 46.8, 42.0, 41.8, 40.6, 37.9, 37.6,36.4, 34.2, 33.5, 29.7, 29.5, 29.5, 27.6, 25.1, 21.3, 21.1, 19.8, 19.4,16.5, 15.9, 14.6.

Step 3. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4,5-dimethylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-thioureido-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(150 mg, 0.249 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine(0.173 mL, 0.995 mmol) and 3-bromobutan-2-one (56.4 mg, 0.373 mmol). Thereaction mixture was stirred at rt. After 18 h, the reaction mixture waspoured into a separatory funnel containing H₂O (10 mL) and extractedwith EtOAc (50 mL). The organic layer was washed with brine, dried overMgSO₄, filtered and concentrated to white solid. The material wasredissolved in DCM (5 mL) and MeOH was added to effect precipitation.The mixture was concentrated to remove most of DCM and the resultingwhite precipitate was filtered, washed with cold MeOH, and dried in avacuum oven to give methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4,5-dimethylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(121 mg, 0.175 mmol, 70.5% yield) as a white solid. LCMS: m/e 655.3(M+H)⁺, 2.72 min (method 2). ¹H NMR (500 MHz, CHLOROFORM-d) δ 7.95 (d,J=8.2 Hz, 2H), 7.21 (d, J=8.2 Hz, 2H), 5.31 (d, J=4.6 Hz, 1H), 4.76 (br.s., 1H), 4.65 (s, 1H), 3.93 (s, 3H), 2.43 (d, J=10.4 Hz, 1H), 2.21 (s,3H), 2.15 (s, 3H), 2.11 (d, J=6.7 Hz, 1H), 2.07-1.96 (m, 1H), 1.80-1.65(m, 6H), 1.57-1.36 (m, 8H), 1.35-1.27 (m, 2H), 1.23 (d, J=10.1 Hz, 1H),1.17-1.11 (m, 1H), 1.09 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H), 0.94 (s,6H).

Step 4. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4,5-dimethylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4,5-dimethylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(107 mg, 0.163 mmol) in THF (3 mL) was added a solution of lithiumhydroxide monohydrate (20.57 mg, 0.490 mmol) in water (1.000 mL). Thereaction was heated to 75° C. for 6 h. The reaction mixture wasconcentrated, redissolved in MeOH (2 mL) and THF (1 mL) filtered and wasthen injected (2 injections) into reverse phase HPLC for purificationusing Prep HPLC method 3 to give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4,5-dimethylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA (58.3 mg, 0.073 mmol, 44.4% yield) as a white solid. LCMS: m/e641.3 (M+H)⁺, 2.51 min (method 2). ¹H NMR (500 MHz, CHLOROFORM-d) δ10.10 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 5.33 (d,J=4.6 Hz, 1H), 4.84 (s, 1H), 4.69 (s, 1H), 2.97 (dt, J=5.2, 11.0 Hz,1H), 2.48 (d, J=13.7 Hz, 1H), 2.32-2.25 (m, 2H), 2.23 (s, 3H), 2.20 (s,3H), 2.16 (dd, J=6.4, 17.1 Hz, 1H), 2.03-1.89 (m, 1H), 1.89-1.79 (m,2H), 1.74 (s, 3H), 1.71 (br. s., 1H), 1.60-1.34 (m, 11H), 1.26-1.19 (m,1H), 1.12 (d, J=13.4 Hz, 1H), 1.06 (s, 3H), 1.03 (s, 3H), 1.01 (s, 3H),0.96 (s, 3H), 0.94 (s, 3H). ¹³C NMR (126 MHz, CHLOROFORM-d) δ 171.0,164.9, 149.8, 148.9, 146.2, 132.4, 130.3, 129.2, 127.0, 124.4, 117.7,111.4, 110.7, 68.1, 53.1, 50.3, 49.8, 45.4, 41.9, 40.8, 37.6, 36.5,36.4, 33.8, 33.1, 29.6, 27.3, 25.3, 21.2, 19.9, 19.6, 16.5, 15.7, 14.5,11.4, 10.8.

Examples 184A and 184B Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((4-ethylthiazol-2-yl)(2-oxobutyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid and4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-ethylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((4-ethylthiazol-2-yl)(2-oxobutyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoateand methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-ethylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-thioureido-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(158 mg, 0.262 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine(0.183 mL, 1.048 mmol) and 1-bromobutan-2-one (0.042 mL, 0.393 mmol).The reaction mixture was stirred at rt. After 16 h, the reaction mixturewas poured into H₂O (5 mL) and extracted with EtOAc (50 mL). The organiclayer was washed with brine, dried over MgSO₄, filtered andconcentrated. The crude material was dissolved in DCM and treated withMeOH to effect precipitation. The mixture was concentrated to remove allDCM and the resulting white precipitate was filtered and washed withMeOH. The product was dried in a vacuum oven to give a mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((4-ethylthiazol-2-yl)(2-oxobutyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoateand methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-ethylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoateas a white solid in quantitative yield (173 mg, 0.264 mmol). LC/MS: m/e725.4 (M+H)⁺, 2.70 min and m/e 655.3 (M+H)⁺, 2.95 min (method 9),respectively. Reversed phased analytical HPLC showed ratio of majorproduct with rt=23.45 min (m/e 655.3 (M+H)⁺) to minor product withrt=26.86 min (m/e 725.4 (M+H)⁺) of 82%:18% (using analytical HPLC method1).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((4-ethylthiazol-2-yl)(2-oxobutyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA and4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-ethylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA

To a mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((4-ethylthiazol-2-yl)(2-oxobutyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoateand methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-ethylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatein THF (3 mL) was added a solution of Li.HO. H₂O (32.7 mg, 0.779 mmol)in water (1.50 mL). The reaction was heated to 75° C. for 6 h. Thereaction mixture was concentrated, redissolved in MeOH (2 mL) and THF (1mL) filtered and was then injected (2 injections) into reverse phaseHPLC for purification using Prep HPLC method 3 to give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((4-ethylthiazol-2-yl)(2-oxobutyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA (22.3 mg, 0.027 mmol, 10.31% yield) and4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-ethylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA (91.7 mg, 0.118 mmol, 45.4% yield) both as a white solid.

Example 184A: LC/MS: m/e 711.4 (M+H)⁺, 2.45 min (method 11), ¹H NMR (500MHz, CHLOROFORM-d) δ 8.14 (br. s., 1H), 7.97 (d, J=7.9 Hz, 2H), 7.21 (d,J=8.2 Hz, 2H), 6.56-6.45 (m, 1H), 6.32 (s, 1H), 5.26 (d, J=5.2 Hz, 1H),5.16 (d, J=19.5 Hz, 1H), 4.84 (s, 1H), 4.67 (br. s., 1H), 3.11-2.98 (m,1H), 2.89-2.77 (m, 1H), 2.73-2.61 (m, 2H), 2.54-2.47 (m, 1H), 2.43 (dd,J=7.6, 16.2 Hz, 1H), 2.30-2.22 (m, 1H), 2.21-2.11 (m, 1H), 2.11-1.98 (m,2H), 1.95-1.87 (m, 1H), 1.71 (s, 3H), 1.63 (d, J=16.2 Hz, 2H), 1.51 (d,J=11.0 Hz, 2H), 1.48-1.37 (m, 6H), 1.34-1.25 (m, 6H), 1.23-1.19 (m, 1H),1.16 (t, J=7.2 Hz, 3H), 1.11 (d, J=10.7 Hz, 1H), 1.00 (br. s., 3H), 0.99(br. s., 3H), 0.96 (br. s., 6H), 0.95 (br. s., 2H). ¹³C NMR (126 MHz,CHLOROFORM-d) δ 203.2, 170.6, 167.1, 149.4, 148.6, 146.3, 144.3, 130.2,129.1, 127.8, 124.6, 110.7, 100.1, 70.7, 55.2, 53.0, 50.7, 49.4, 44.3,42.0, 41.8, 40.7, 37.6, 36.4, 36.3, 33.6, 33.4, 32.7, 29.6, 29.4, 27.3,27.2, 25.2, 21.5, 21.2, 20.7, 19.8, 19.7, 16.5, 15.5, 14.5, 10.8, 7.3.

Example 184B: LC/MS: m/e 641.3 (M+H)⁺, 2.51 min (method 11), ¹H NMR (500MHz, CHLOROFORM-d) δ 10.17 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.25 (d,J=8.2 Hz, 2H), 6.07 (s, 1H), 5.33 (d, J=4.6 Hz, 1H), 4.85 (s, 1H), 4.70(s, 1H), 2.97 (dt, J=5.0, 11.1 Hz, 1H), 2.71 (dq, J=0.9, 7.5 Hz, 2H),2.53-2.45 (m, 1H), 2.32 (dd, J=7.8, 13.0 Hz, 1H), 2.26 (dt, J=2.9, 12.1Hz, 1H), 2.16 (dd, J=6.3, 17.2 Hz, 1H), 2.05-1.92 (m, 1H), 1.90-1.79 (m,2H), 1.74 (s, 3H), 1.69 (d, J=16.8 Hz, 1H), 1.60-1.35 (m, 11H), 1.30 (t,J=7.6 Hz, 3H), 1.23 (dd, J=4.1, 9.6 Hz, 1H), 1.13 (d, J=13.1 Hz, 1H),1.06 (s, 3H), 1.03 (s, 3H), 1.01 (s, 3H), 0.96 (s, 3H), 0.95 (s, 3H).¹³C NMR (126 MHz, CHLOROFORM-d) δ 171.5, 167.1, 163.3, 163.0, 149.8,148.8, 146.2, 144.6, 130.3, 129.3, 127.1, 124.4, 117.5, 115.2, 110.8,98.3, 68.3, 53.1, 50.3, 49.7, 45.4, 41.9, 40.8, 37.6, 36.5, 36.4, 33.8,32.8, 29.6, 27.3, 27.1, 25.3, 21.7, 21.2, 19.8, 19.6, 16.5, 15.7, 14.5,11.8.

Example 185 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-tert-butylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-tert-butylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-thioureido-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(150 mg, 0.249 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine(0.217 mL, 1.244 mmol) and 1-bromopinacolone (0.056 mL, 0.373 mmol). Thereaction mixture was stirred at rt overnight. After 18 h, the reactionmixture was poured into a separatory funnel containing H₂O (5 mL) andextracted with EtOAc (50 mL). The organic layer was washed with brine,dried over MgSO₄, filtered and concentrated to white solid. The materialwas redissolved in DCM (3 mL), MeOH wash added and concentrated toremove most of the DCM. The resulting white precipitate was filtered,washed with cold MeOH, and dried in a vacuum oven to give methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-tert-butylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(154.0 mg, 0.225 mmol, 91% yield) as a white solid. LC/MS: m/e 683.4(M+H)⁺, 2.88 min (method 11). ¹H NMR (500 MHz, CHLOROFORM-d) δ 7.95 (d,J=8.2 Hz, 2H), 7.22 (d, J=8.2 Hz, 2H), 6.06 (s, 1H), 5.31 (d, J=4.6 Hz,1H), 4.88 (s, 1H), 4.77 (s, 1H), 4.66 (s, 1H), 3.93 (s, 3H), 2.72 (d,J=13.7 Hz, 1H), 2.68-2.62 (m, 1H), 2.55 (dd, J=8.1, 12.7 Hz, 1H), 2.13(dd, J=6.4, 17.1 Hz, 1H), 2.07-1.98 (m, 1H), 1.92-1.83 (m, 1H),1.82-1.76 (m, 1H), 1.74 (s, 3H), 1.73-1.66 (m, 2H), 1.61 (s, 1H),1.57-1.49 (m, 3H), 1.49-1.40 (m, 4H), 1.40-1.31 (m, 3H), 1.29 (s, 9H),1.27-1.21 (m, 1H), 1.18-1.12 (m, 1H), 1.10 (s, 3H), 1.04 (s, 3H), 1.01(s, 3H), 0.95 (s, 6H).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-tert-butylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-tert-butylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(139 mg, 0.204 mmol) in THF (3 mL) was added a solution of lithiumhydroxide monohydrate (25.6 mg, 0.611 mmol) in water (1 mL). Thereaction was heated to 75° C. for 6 h. The reaction mixture wasconcentrated, redissolved in MeOH (2 mL) and THF (1 mL) filtered and wasthen injected (2 injections) into reverse phase HPLC for purificationusing Prep HPLC method 3 to give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-tert-butylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA (49.3 mg, 0.059 mmol, 28.8% yield) as a white solid. LC/MS:m/e 669.4 (M+H)⁺, 2.61 min (method 11). ¹H NMR (500 MHz, CHLOROFORM-d) δ8.02 (d, J=7.9 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 6.05 (s, 1H), 5.33 (d,J=4.9 Hz, 1H), 4.86 (s, 1H), 4.70 (s, 1H), 3.52 (s, 1H), 3.03 (dt,J=5.0, 10.9 Hz, 1H), 2.54 (d, J=14.0 Hz, 1H), 2.34 (dd, J=8.1, 12.7 Hz,1H), 2.31-2.22 (m, 1H), 2.16 (dd, J=6.3, 17.2 Hz, 1H), 2.09-1.96 (m,1H), 1.92-1.80 (m, 2H), 1.75 (s, 3H), 1.69 (d, J=16.8 Hz, 1H), 1.58 (br.S., 1H), 1.53-1.42 (m, 8H), 1.39 (s, 9H), 1.28 (s, 2H), 1.23 (d, J=9.2Hz, 2H), 1.13 (d, J=13.7 Hz, 1H), 1.08 (s, 4H), 1.04 (s, 3H), 1.01 (s,3H), 0.95 (br. S., 3H), 0.95 (br. S., 3H). ¹³C NMR (126 MHz,CHLOROFORM-d) δ 170.9, 167.4, 151.7, 149.5, 148.3, 145.6, 129.9, 128.8,126.5, 124.0, 110.5, 96.6, 68.0, 52.7, 50.0, 49.3, 44.9, 41.5, 41.5,40.3, 37.2, 36.1, 36.0, 33.5, 33.4, 32.3, 29.2, 29.2, 28.5, 27.0, 26.8,24.9, 20.8, 20.7, 19.4, 19.3, 16.1, 15.4, 14.1.

Example 186 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(4-(thiophen-3-yl)thiazol-2-ylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid and4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-oxo-2-(thiophen-3-yl)ethyl)(4-(thiophen-3-yl)thiazol-2-yl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(4-(thiophen-3-yl)thiazol-2-ylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoateand methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-oxo-2-(thiophen-3-yl)ethyl)(4-(thiophen-3-yl)thiazol-2-yl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-thioureido-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(150 mg, 0.249 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine(0.217 mL, 1.244 mmol) and 2-bromo-1-(thiophen-3-yl)ethanone (77 mg,0.373 mmol). The reaction mixture was stirred at rt overnight. After 18h, the reaction mixture was poured into a separatory funnel containingH₂O (5 mL) and extracted with EtOAc (50 mL). The organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated to whitesolid. The material was redissolved in DCM (3 mL). MeOH was added andthe mixture was concentrated to remove most of DCM. The resulting whiteprecipitate was filtered, washed with cold MeOH, and dried in a vacuumoven to give a 4:1 mixture of (as determined by HPLC integration) methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(4-(thiophen-3-yl)thiazol-2-ylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoateand methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-oxo-2-(thiophen-3-yl)ethyl)(4-(thiophen-3-yl)thiazol-2-yl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(134 mg, 82% yield) as white solid. LC/MS: m/e 709.3 (M+H)⁺, 3.62 minand m/e 833.3 (M+H)⁺, 2.63 min (method 9), respectively. Reverse phasedanalytical HPLC showed ratio of major product with rt=16.04 min (m/e709.3 (M+H)⁺) to minor product with rt=15.42 min (m/e 833.3 (M+H)⁺)product of 80%:20% (using analytical HPLC method 2).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(4-(thiophen-3-yl)thiazol-2-ylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA and4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-oxo-2-(thiophen-3-yl)ethyl)(4-(thiophen-3-yl)thiazol-2-yl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA

To a mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(4-(thiophen-3-yl)thiazol-2-ylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(119.36 mg, 0.168 mmol) and methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-oxo-2-(thiophen-3-yl)ethyl)(4-(thiophen-3-yl)thiazol-2-yl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(29.84 mg, 0.036 mmol) in THF (3 mL) was added a solution of lithiumhydroxide monohydrate (25.4 mg, 0.606 mmol) in water (1 mL). Thereaction was heated to 75° C. for 6 h. The reaction mixture wasconcentrated, redissolved in MeOH (2 mL) and THF (1 mL) filtered and wasthen injected (2 injections) onto reverse phase HPLC for purificationusing Prep HPLC method 3 to give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(4-(thiophen-3-yl)thiazol-2-ylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA (110.7 mg, 0.134 mmol, 80% yield) and4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-oxo-2-(thiophen-3-yl)ethyl)(4-(thiophen-3-yl)thiazol-2-yl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA (13.4 mg, 0.016 mmol, 9.52% yield).

Example 186: LC/MS: m/e 695.3 (M+H)⁺, 2.92 min (method 11). ¹H NMR (500MHz, CHLOROFORM-d) δ 8.12 (br. s., 1H), 8.03 (d, J=8.2 Hz, 2H),7.42-7.39 (m, 1H), 7.38-7.36 (m, 1H), 7.25 (d, J=8.2 Hz, 2H), 6.52 (s,1H), 5.33 (d, J=4.6 Hz, 1H), 4.86 (s, 1H), 4.71 (s, 1H), 3.04 (dt,J=5.0, 11.1 Hz, 1H), 2.58 (d, J=14.0 Hz, 1H), 2.39 (dd, J=7.9, 12.8 Hz,1H), 2.33-2.25 (m, 1H), 2.15 (dd, J=6.4, 17.1 Hz, 1H), 2.06-1.98 (m,1H), 1.92-1.82 (m, 2H), 1.76 (s, 3H), 1.70 (d, J=17.1 Hz, 1H), 1.64-1.56(m, 1H), 1.55-1.47 (m, 5H), 1.46-1.37 (m, 5H), 1.23 (d, J=10.1 Hz, 1H),1.15 (d, J=13.1 Hz, 1H), 1.06 (s, 3H), 1.05 (s, 3H), 0.99 (s, 3H), 0.95(s, 3H), 0.94 (s, 3H). ¹³C NMR (126 MHz, CHLOROFORM-d) δ 171.2, 167.1,163.3, 149.3, 148.5, 145.9, 129.9, 128.8, 127.0, 126.9, 124.7, 124.4,123.9, 117.4, 115.1, 110.4, 98.1, 68.0, 52.6, 50.0, 49.3, 45.0, 41.6,41.5, 40.4, 37.2, 36.2, 36.0, 33.4, 32.6, 29.2, 29.2, 27.0, 26.9, 24.9,20.8, 19.5, 19.2, 16.1, 15.3, 14.1.

Example 186A: LC/MS: m/e 818.4 (M+H)⁺, 2.50 min (method 11).

Examples 187 and 187A Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(4-(pyridin-2-yl)thiazol-2-ylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid and4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-oxo-2-(pyridin-2-yl)ethyl)(4-(pyridin-2-yl)thiazol-2-yl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(4-(pyridin-2-yl)thiazol-2-ylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoateand methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-oxo-2-(pyridin-2-yl)ethyl)(4-(pyridin-2-yl)thiazol-2-yl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-thioureido-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(150 mg, 0.249 mmol) was added N,N-diisopropylethylamine (0.217 mL,1.244 mmol) and 2-bromo-1-(pyridin-2-yl)ethanone, hydrobromide (116 mg,0.373 mmol). The reaction mixture was stirred at rt overnight. After 18h, the reaction mixture was poured into a separatory funnel containingH₂O (5 mL) and extracted with EtOAc (50 mL). The organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated to brownsolid. The material was redissolved in DCM (3 mL), MeOH was added andthe resulting mixture was concentrated to remove most of DCM. Theresulting white precipitate was filtered, washed with cold MeOH, anddried in a vacuum oven to give a 91:9 mixture (as determined by HPLCintegration) of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(4-(pyridin-2-yl)thiazol-2-ylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoateand methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-oxo-2-(pyridin-2-yl)ethyl)(4-(pyridin-2-yl)thiazol-2-yl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(137 mg, 76.57% yield) as brown solid. LC/MS: m/e 704.3 (M+H)⁺, 3.72 minand m/e 823.4 (M+H)⁺, 2.56 min (method 9), respectively. Reversed phasedanalytical HPLC showed ratio of major product with rt=22.43 min (m/e704.3 (M+H)⁺) to minor product with rt=23.61 min (m/e 823.4 (M+H)⁺)product of 91%:9% (using analytical HPLC method 1).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(4-(pyridin-2-yl)thiazol-2-ylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA and4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-oxo-2-(pyridin-2-yl)ethyl)(4-(pyridin-2-yl)thiazol-2-yl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA

To a mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(4-(pyridin-2-yl)thiazol-2-ylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(117.66 mg, 0.167 mmol) and methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-oxo-2-(pyridin-2-yl)ethyl)(4-(pyridin-2-yl)thiazol-2-yl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(19.6 mg, 0.024 mmol) in THF (3 mL) was added a solution of lithiumhydroxide monohydrate (25.2 mg, 0.602 mmol) in water (1 mL). Thereaction was heated to 75° C. for 6 h. The reaction mixture wasconcentrated, redissolved in MeOH (2 mL) and THF (1 mL) filtered and wasinjected onto reverse phase HPLC for purification using Prep HPLC method3 to give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(4-(pyridin-2-yl)thiazol-2-ylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA (70.2 mg, 0.085 mmol, 50.7% yield) and4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-oxo-2-(pyridin-2-yl)ethyl)(4-(pyridin-2-yl)thiazol-2-yl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, TFA (10.3 mg, 0.011 mmol, 6.86% yield).

Example 187: LC/MS: m/e 690.3 (M+H)⁺, 2.53 min (method 11). ¹H NMR (500MHz, CHLOROFORM-d) δ 9.67 (br. s., 1H), 8.73 (td, J=0.9, 5.0 Hz, 1H),8.14 (d, J=7.9 Hz, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.96 (dt, J=1.7, 7.9 Hz,1H), 7.42 (s, 1H), 7.40 (ddd, J=0.9, 4.9, 7.6 Hz, 1H), 7.25 (d, J=8.5Hz, 2H), 5.33 (d, J=4.6 Hz, 1H), 4.86 (s, 1H), 4.71 (s, 1H), 2.99 (dt,J=4.9, 11.0 Hz, 1H), 2.64-2.58 (m, 1H), 2.41 (dd, J=8.1, 12.7 Hz, 1H),2.23 (dt, J=3.1, 12.1 Hz, 1H), 2.16 (dd, J=6.3, 17.2 Hz, 1H), 2.06-2.00(m, 1H), 1.90 (t, J=11.7 Hz, 1H), 1.85 (d, J=12.5 Hz, 1H), 1.76 (s, 3H),1.70 (d, J=17.1 Hz, 1H), 1.64-1.55 (m, 1H), 1.55-1.39 (m, 9H), 1.30-1.21(m, 1H), 1.17 (d, J=13.1 Hz, 1H), 1.08 (s, 3H), 1.06 (s, 3H), 1.01 (s,3H), 0.95 (s, 3H), 0.95 (s, 3H). ¹³C NMR (126 MHz, CHLOROFORM-d) δ170.8, 167.4, 149.3, 148.4, 146.3, 145.9, 141.1, 138.6, 129.9, 128.8,126.8, 123.9, 123.9, 121.2, 110.4, 104.8, 77.3, 68.1, 52.6, 49.9, 49.3,45.2, 41.6, 41.5, 40.4, 37.2, 36.5, 36.0, 33.3, 32.7, 29.2, 29.2, 26.9,24.9, 20.8, 19.4, 19.2, 16.1, 15.4, 14.2.

Example 187A: LC/MS: m/e 809.5 (M+H)⁺, 2.38 min (method 11).

Example 188 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridin-2-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

In a 1 dram vial under nitrogen were combined(2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene(CAS#158923-11-6) (2.101 mg, 3.79 μmol), palladium(II) acetate (0.851mg, 3.79 μmol) and dry DME (0.5 ml). The contents of the vial werestirred for 10 min, and were then added all at once to a separatemixture of 2-bromopyridine (0.012 g, 0.076 mmol) and sodiumtert-butoxide (0.032 g, 0.333 mmol) in dry DME (0.5 mL) contained in aseparate 1 dram vial. The resulting mixture was allowed to stir verybriefly (1 min) before TBDMSCl (0.025 g, 0.167 mmol) was added. The vialwas shaken briefly, and solid methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-aminoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatebis HCl salt (0.050 g, 0.076 mmol) was added in one portion. A mildexotherm resulted upon the final addition. The mixture was heated to110° C. for 15 min. LCMS indicated essentially complete consumption ofstarting material. To the mixture was added water (0.5 mL) and methanol(1.5 mL) and the resulting mixture was stirred for 2 days. Purificationof the crude mixture by reverse phase preparative HPLC using Prep HPLCMethod 6 gave the title compound (0.0092 g, 13.1% yield) as a beigepowder bis TFA salt. LCMS: m/e 650.4 (M+H)⁺, 3.76 min (method 16). ¹HNMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 8.01 (d,J=4.9 Hz, 1H), 7.95-7.88 (m, J=8.2 Hz, 2H), 7.72 (t, J=7.3 Hz, 1H),7.23-7.16 (m, J=8.2 Hz, 2H), 6.92 (d, J=8.2 Hz, 1H), 6.85 (t, J=6.3 Hz,1H), 5.29 (d, J=4.9 Hz, 1H), 4.86 (s, 1H), 4.74 (br. s., 1H), 3.90-3.72(m, 2H), 3.23-3.14 (m, 1H), 2.78-2.67 (m, 1H), 2.17-2.04 (m, 2H),2.03-1.82 (m, 5H), 1.73 (s, 3H), 1.71-1.66 (m, 1H), 1.65-1.46 (m, 6H),1.45-1.22 (m, 9H), 1.21-1.09 (m, 1H), 1.06 (s, 3H), 0.99 (br. s., 3H),0.98 (br. s., 3H), 0.94 (s, 3H), 0.93 (br. s., 3H), 0.91-0.84 (m, J=6.7,3.4 Hz, 1H).

Example 189 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

In a 1 dram vial under nitrogen were combined(2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene(CAS#158923-11-6) (2.101 mg, 3.79 μmol), palladium(II) acetate (0.851mg, 3.79 mmol) and dry DME (0.5 ml). The contents of the vial werestirred for 10 min, and were then added all at once to a separatemixture of 3-bromopyridine (0.014 g, 0.091 mmol) and sodiumtert-butoxide, 2.0M solution in THF (0.167 mL, 0.333 mmol) in dry DME(0.333 mL) contained in a separate 1 dram vial. The resulting mixturewas allowed to stir very briefly (1 min) before solid methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-aminoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatebis HCl salt (0.050 g, 0.076 mmol) was added in one portion. The mixturewas heated to 110° C. overnight. To the mixture was added lithiumhydroxide monohydrate (6.4 mg, 0.152 mmol) with water (0.2 mL) andmethanol (0.5 mL) and the resulting mixture was stirred for 4 days.Purification of the crude mixture by reverse phase preparative HPLCusing Prep HPLC Method 7 gave the title compound (0.0407 g, 57.5% yield)as a beige powder bis TFA salt. LCMS: m/e 650.4 (M+H)⁺, 2.26 min (method11). ¹H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm8.26 (d, J=2.4 Hz, 1H), 8.02 (d, J=4.9 Hz, 1H), 7.94-7.87 (m, J=8.2 Hz,2H), 7.77 (dd, J=8.9, 1.5 Hz, 1H), 7.67 (dd, J=8.9, 5.2 Hz, 1H),7.22-7.14 (m, 2H), 5.28 (dd, J=6.3, 1.7 Hz, 1H), 4.82 (s, 1H), 4.74 (s,1H), 3.89-3.78 (m, 1H), 3.70 (dt, J=14.6, 4.5 Hz, 1H), 3.30-3.23 (m,2H), 2.85 (td, J=11.1, 5.5 Hz, 1H), 2.21-2.05 (m, 3H), 2.03-1.94 (m,2H), 1.94-1.85 (m, 1H), 1.85-1.76 (m, 1H), 1.72 (s, 3H), 1.70-1.64 (m,1H), 1.64-1.51 (m, 3H), 1.51-1.44 (m, 3H), 1.43-1.20 (m, 6H), 1.19-1.08(m, 2H), 1.07-1.04 (m, 3H), 1.04-1.00 (m, 3H), 0.99 (s, 3H), 0.95-0.88(m, 7H).

Example 190 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridin-4-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following a similar procedure asdescribed for the synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 4-bromopyridine hydrochloride (0.018 g, 0.091 mmol) wasused in place of 3-bromopyridine, and an additional 1.2 equivalents ofsodium tert-butoxide, 2.0M solution in THF (for a total of 5.6equivalents, 0.212 mL, 0.424 mmol) was employed. The product wasisolated after reverse phase preparative HPLC purification using PrepHPLC Method 7 as a beige solid (74 mg, 54% yield) bis TFA salt. LCMS:m/e 650.4 (M+H)⁺, 3.85 min (method 16). ¹H NMR (500 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm 8.19-7.97 (m, 2H), 7.91 (d, J=8.2 Hz,2H), 7.19 (d, J=8.2 Hz, 2H), 7.06 (br. s., 2H), 5.28 (d, J=4.6 Hz, 1H),4.83 (s, 1H), 4.73 (s, 1H), 3.96-3.81 (m, 2H), 3.31-3.19 (m, 2H),2.88-2.76 (m, 1H), 2.18-2.03 (m, 3H), 1.97 (dd, J=10.4, 6.4 Hz, 3H),1.83 (d, J=12.5 Hz, 1H), 1.72 (s, 3H), 1.68 (br. s., 1H), 1.66-1.45 (m,7H), 1.44-1.28 (m, 5H), 1.24 (d, J=8.2 Hz, 1H), 1.18-1.11 (m, 1H), 1.09(s, 3H), 1.06 (s, 3H), 1.01 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H).

Example 191 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(1-methyl-1H-imidazol-2-ylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following a similar procedure asdescribed for the synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-bromo-1-methyl-1H-imidazole (0.015 g, 8.88 μL, 0.091mmol) was used in place of 3-bromopyridine. Also, addition of LiOH,water and methanol were unnecessary for this example, as the esterhydrolysis occurred spontaneously during the course of the aminationreaction. The product was isolated after reverse phase preparative HPLCpurification using Prep HPLC Method 8 as a beige solid (38.1 mg, 51.5%yield) bis TFA salt. LCMS: m/e 653.4 (M+H)⁺, 3.88 min (method 16). ¹HNMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 7.91 (d,J=8.2 Hz, 2H), 7.19 (d, J=7.9 Hz, 2H), 6.86 (s, 1H), 6.83-6.79 (m, 1H),5.28 (d, J=5.5 Hz, 1H), 4.84 (s, 1H), 4.73 (s, 1H), 4.71 (br. s., 1H),3.98-3.82 (m, 2H), 3.58 (s, 3H), 3.25 (br. s., 1H), 2.89-2.78 (m, 1H),2.18-2.07 (m, 3H), 2.05-1.92 (m, 3H), 1.90-1.79 (m, 1H), 1.72 (s, 4H),1.69 (br. s., 1H), 1.62-1.54 (m, 3H), 1.53-1.47 (m, 3H), 1.46-1.34 (m,5H), 1.28-1.20 (m, 2H), 1.18-1.12 (m, 1H), 1.11 (s, 3H), 1.09-1.03 (m,4H), 1.01 (s, 3H), 0.93 (br. s., 3H), 0.93 (br. s., 3H).

Example 192 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(phenylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following a similar procedure asdescribed for the synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except bromobenzene (0.014 g, 9.58 μL, 0.091 mmol) was used inplace of 3-bromopyridine. The product was isolated after reverse phasepreparative HPLC purification using Prep HPLC Method 7 as a beige solid(29.7 mg, 42% yield) bis TFA salt. LCMS: m/e 649.4 (M+H)⁺, 2.42 min(method 11). ¹H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock)δ ppm 7.94-7.88 (m, J=7.9 Hz, 2H), 7.22 (t, J=7.8 Hz, 2H), 7.20-7.15 (m,J=8.2 Hz, 2H), 6.82 (t, J=7.3 Hz, 1H), 6.75 (d, J=7.9 Hz, 2H), 5.27 (d,J=5.5 Hz, 1H), 4.81 (s, 1H), 4.73 (s, 1H), 3.68-3.58 (m, 1H), 3.58-3.51(m, 1H), 3.25-3.17 (m, 2H), 2.82 (td, J=11.0, 5.2 Hz, 1H), 2.18-2.05 (m,2H), 2.01-1.92 (m, 2H), 1.90 (br. s., 1H), 1.83-1.72 (m, 2H), 1.71 (s,3H), 1.68 (d, J=17.4 Hz, 1H), 1.64-1.46 (m, 6H), 1.45-1.30 (m, 5H),1.27-1.11 (m, 4H), 1.10-1.02 (m, 2H), 1.02-0.99 (m, 6H), 0.98 (s, 3H),0.93 (s, 3H), 0.91 (s, 3H).

Example 193 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(thiazol-2-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following a similar procedure asdescribed for the synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-bromothiazole (0.015 g, 0.091 mmol) was used in place of3-bromopyridine. The product was isolated after reverse phasepreparative HPLC purification using Prep HPLC Method 7 as a beige solid(12.8 mg, 18% yield) bis TFA salt. LCMS: m/e 656.4 (M+H)⁺, 2.38 min(method 11). ¹H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock)δ ppm 7.91 (d, J=8.2 Hz, 2H), 7.19 (d, J=8.2 Hz, 2H), 7.08 (d, J=3.7 Hz,1H), 6.68 (d, J=4.0 Hz, 1H), 5.28 (d, J=4.6 Hz, 1H), 4.86 (s, 1H), 4.74(br. s., 1H), 3.69 (dd, J=9.9, 5.3 Hz, 1H), 3.43-3.36 (m, 1H), 2.13 (dd,J=17.2, 6.3 Hz, 1H), 2.05 (d, J=15.0 Hz, 1H), 2.01-1.79 (m, 6H), 1.73(s, 4H), 1.70-1.46 (m, 8H), 1.46-1.27 (m, 6H), 1.27-1.22 (m, 2H),1.22-1.10 (m, 2H), 1.07 (s, 3H), 1.04 (s, 3H), 1.00 (s, 3H), 0.93 (s,3H), 0.92 (s, 3H).

Example 194 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(6-methylpyridazin-3-ylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

In a 1 dram vial under nitrogen were combined(2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene(CAS#158923-11-6) (2.52 mg, 4.55 mmol), palladium(II) acetate (1.02 mg,4.55 mmol) and dry DME (0.5 ml). The contents of the vial were stirredfor 10 min, and were then added all at once to a separate mixture of3-bromo-6-methylpyridazine (0.017 g, 0.100 mmol) and sodiumtert-butoxide, 2.0M solution in THF (0.200 mL, 0.400 mmol) in dry DME(0.500 mL) contained in a separate 1 dram vial. The resulting mixturewas allowed to stir very briefly (1 min) before solid methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-aminoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatebis HCl salt (0.060 g, 0.091 mmol) was added in one portion. The mixturewas heated to 110° C. overnight. Iterative purification of the crudemixture by reverse phase preparative HPLC first using Prep HPLC Method 9and then repurification by Prep HPLC Method 10 gave the title compound(0.0070 g, 8.3% yield) as a white glassy solid bis TFA salt. LCMS: m/e665.5 (M+H)⁺, 2.22 min (method 11). ¹H NMR (500 MHz, 1:1 mixture ofCDCl3 and MeOD, MeOD lock) δ ppm 7.90 (d, J=8.5 Hz, 2H), 7.49-7.42 (m,1H), 7.32-7.23 (m, 1H), 7.18 (d, J=8.2 Hz, 2H), 5.27 (dd, J=6.0, 1.4 Hz,1H), 4.88 (br. s., 1H), 4.72 (br. s., 1H), 3.94-3.84 (m, 1H), 3.84-3.73(m, 1H), 3.26-3.13 (m, 1H), 2.84 (d, J=12.5 Hz, 1H), 2.57 (s, 3H), 2.12(dd, J=16.9, 6.3 Hz, 1H), 2.05 (d, J=15.6 Hz, 1H), 2.01-1.91 (m, 2H),1.91-1.74 (m, 2H), 1.70 (s, 3H), 1.69-1.59 (m, 2H), 1.59-1.43 (m, 4H),1.43-1.28 (m, 4H), 1.28-1.18 (m, 4H), 1.18-1.06 (m, 2H), 1.05 (s, 3H),0.99 (s, 3H), 0.97 (s, 3H), 0.92 (s, 3H), 0.92-0.89 (m, 3H).

Example 195 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-acetamidoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following a similar procedure asdescribed for the synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(6-methylpyridazin-3-ylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 4-bromopyrimidine (0.016 g, 0.100 mmol) was used in placeof 3-bromo-6-methylpyridazine. The reaction did not produce the intendedproduct but instead produced the byproduct title compound as the majorisolate. Iterative purification of the crude mixture by reverse phasepreparative HPLC first using Prep HPLC Method 9 and then repurificationby Prep HPLC Method 10 gave the title compound as a white glassy solid(7.5 mg, 9.6% yield) mono TFA salt. LCMS: m/e 615.5 (M+H)⁺, 2.42 min(method 11). ¹H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock)δ ppm 8.18 (s, 1H), 7.94-7.84 (m, J=8.2 Hz, 2H), 7.24-7.13 (m, J=8.2 Hz,2H), 5.27 (d, J=4.6 Hz, 1H), 4.83 (s, 1H), 4.72 (br. s., 1H), 3.89 (s,3H), 3.61 (br. s., 2H), 3.18 (br. s., 2H), 2.71 (td, J=11.1, 6.3 Hz,2H), 2.12-1.92 (m, 6H), 1.90-1.76 (m, 3H), 1.76-1.66 (m, 5H), 1.66-1.43(m, 9H), 1.42-1.33 (m, 3H), 1.24 (br. s., 2H), 1.17 (s, 3H), 1.07 (s,3H), 1.01 (s, 3H), 0.93 (s, 3H), 0.92 (br. s., 3H).

Example 196 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(5-(methylthio)pyridin-2-ylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following a similar procedure asdescribed for the synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(6-methylpyridazin-3-ylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-bromo-5-(methylthio)pyridine (0.020 g, 0.100 mmol) wasused in place of 3-bromo-6-methylpyridazine. Iterative purification ofthe crude mixture by reverse phase preparative HPLC first using PrepHPLC Method 9 and then repurification by Prep HPLC Method 10 gave thetitle compound as a white glassy solid (5.2 mg, 5.9% yield) bis TFAsalt. LCMS: m/e 696.5 (M+H)⁺, 2.34 min (method 11). ¹H NMR (500 MHz, 1:1mixture of CDCl3 and MeOD, MeOD lock) δ ppm 8.03 (d, J=1.8 Hz, 1H),7.93-7.88 (m, J=8.2 Hz, 2H), 7.61-7.57 (m, 1H), 7.21-7.14 (m, J=8.2 Hz,2H), 6.71 (d, J=8.9 Hz, 1H), 5.27 (dd, J=6.1, 1.5 Hz, 1H), 4.87 (s, 1H),4.75 (br. s., 1H), 4.72 (br. s., 1H), 3.80-3.72 (m, 1H), 3.72-3.63 (m,1H), 3.18-3.09 (m, 1H), 2.72-2.64 (m, 1H), 2.39 (s, 3H), 2.11 (dd,J=17.1, 6.4 Hz, 1H), 2.08-2.01 (m, 1H), 2.00-1.90 (m, 3H), 1.90-1.74 (m,3H), 1.72 (s, 3H), 1.71-1.66 (m, 2H), 1.65-1.44 (m, 7H), 1.44-1.33 (m,3H), 1.33-1.12 (m, 7H), 1.04 (s, 3H), 0.97 (s, 3H), 0.91 (br. s., 3H),0.91 (br. s., 3H), 0.87 (s, 3H).

Example 197 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(4-(methylthio)pyrimidin-2-ylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following a similar procedure asdescribed for the synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(6-methylpyridazin-3-ylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-chloro-4-(methylthio)pyrimidine (0.016 g, 0.100 mmol) wasused in place of 3-bromo-6-methylpyridazine. Iterative purification ofthe crude mixture by reverse phase preparative HPLC first using PrepHPLC Method 9 and then repurification by Prep HPLC Method 10 gave thetitle compound as a white glassy solid (12.0 mg, 14% yield) bis TFAsalt. LCMS: m/e 697.5 (M+H)⁺, 2.30 min (method 11). ¹H NMR (500 MHz, 1:1mixture of CDCl3 and MeOD, MeOD lock) δ ppm 7.99-7.85 (m, 3H), 7.17 (d,J=8.2 Hz, 2H), 6.75-6.63 (m, 1H), 5.26 (d, J=4.6 Hz, 1H), 4.82 (s, 1H),4.70 (br. s., 1H), 3.96 (s, 1H), 3.85 (br. s., 2H), 3.43-3.34 (m, 1H),3.25 (br. s., 1H), 2.72 (br. s., 1H), 2.55 (s, 3H), 2.10 (dd, J=17.1,6.4 Hz, 1H), 2.04 (d, J=15.3 Hz, 1H), 2.01-1.89 (m, 3H), 1.89-1.77 (m,2H), 1.70 (s, 4H), 1.68-1.49 (m, 5H), 1.46 (d, J=7.3 Hz, 3H), 1.42-1.18(m, 7H), 1.18-1.06 (m, 2H), 1.03 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H),0.92 (s, 3H), 0.91 (br. s., 3H).

Example 198 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(6-(methylthio)pyridin-2-ylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following a similar procedure asdescribed for the synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(6-methylpyridazin-3-ylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-bromo-6-(methylthio)pyridine (0.020 g, 0.100 mmol) wasused in place of 3-bromo-6-methylpyridazine. Iterative purification ofthe crude mixture by reverse phase preparative HPLC first using PrepHPLC Method 9 and then repurification by Prep HPLC Method 10 gave thetitle compound as a white glassy solid (10.3 mg, 12% yield) bis TFAsalt. LCMS: m/e 696.5 (M+H)⁺, 2.34 min (method 11). ¹H NMR (500 MHz, 1:1mixture of CDCl3 and MeOD, MeOD lock) δ ppm 7.95-7.85 (m, J=8.2 Hz, 2H),7.39 (t, J=7.8 Hz, 1H), 7.20-7.12 (m, J=8.2 Hz, 2H), 6.53 (d, J=7.6 Hz,1H), 6.37 (d, J=7.9 Hz, 1H), 5.25 (d, J=4.6 Hz, 1H), 4.85 (s, 1H), 4.72(br. s., 1H), 3.96 (s, 1H), 3.78-3.59 (m, 2H), 3.28-3.13 (m, 2H),2.95-2.83 (m, 1H), 2.49 (s, 3H), 2.08-1.86 (m, 6H), 1.78-1.69 (m, 4H),1.69-1.52 (m, 5H), 1.52-1.31 (m, 6H), 1.31-1.07 (m, 7H), 1.01 (s, 3H),0.95-0.83 (m, 9H), 0.57 (s, 3H).

Example 199 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyrimidin-2-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following a similar procedure asdescribed for the synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(6-methylpyridazin-3-ylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-bromopyrimidine (0.016 g, 0.100 mmol) was used in placeof 3-bromo-6-methylpyridazine. Iterative purification of the crudemixture by reverse phase preparative HPLC first using Prep HPLC Method 9and then repurification by Prep HPLC Method 10 gave the title compoundas a white glassy solid (8.0 mg, 8.2% yield) bis TFA salt. LCMS: m/e651.5 (M+H)⁺, 2.27 min (method 11).

Example 200 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridazin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridazin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

The title compound was prepared following a similar procedure asdescribed for the synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(6-methylpyridazin-3-ylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 3-chloropyridazine (0.011 g, 0.100 mmol) was used in placeof 3-bromo-6-methylpyridazine. Purification of the crude mixture byreverse phase preparative HPLC using Prep HPLC Method 9 gave the titlecompound as a white glassy solid (4.9 mg, 6.0% yield) bis TFA salt.LCMS: m/e 665.5 (M+H)⁺, 2.40 min (method 11).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridazin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

A solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridazin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoateand lithium hydroxide monohydrate (2.3 mg, 0.055 mmol) in a mixture ofwater (0.5 mL), THF (0.25 mL) and MeOH (0.25 mL) was stirred at rt for2.5 days. Purification of the crude mixture by reverse phase preparativeHPLC using Prep HPLC Method 10 gave the title compound as a white solid(5.0 mg, 100% yield) bis TFA salt. LCMS: m/e 651.5 (M+H)⁺, 2.26 min(method 11).

Example 201 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(5-(methylsulfonyl)pyridin-2-ylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following a similar procedure asdescribed for the synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridazin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid, except 2-bromo-5-(methylsulfonyl)pyridine (0.024 g, 0.100 mmol)was used in place of 3-chloropyridazine. Purification of the crude Step2 mixture by reverse phase preparative HPLC using Prep HPLC Method 10gave the title compound as an off-white solid (10.6 mg, 11.9% yield over2 steps) bis TFA salt. LCMS: m/e 728.5 (M+H)⁺, 2.22 min (method 11). ¹HNMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 8.61 (d,J=1.8 Hz, 1H), 7.95-7.87 (m, 3H), 7.19 (d, J=8.2 Hz, 2H), 6.80 (d, J=8.9Hz, 1H), 5.29 (d, J=4.6 Hz, 1H), 4.90 (s, 1H), 4.82 (br. s., 1H),3.96-3.85 (m, 1H), 3.85-3.71 (m, 1H), 3.42 (br. s., 1H), 3.37 (s, 3H),3.27-3.18 (m, 1H), 3.10 (s, 3H), 2.70 (br. s., 1H), 2.14 (dd, J=17.2,6.3 Hz, 1H), 2.10-1.95 (m, 5H), 1.91-1.77 (m, 3H), 1.74 (s, 3H), 1.71(d, J=17.4 Hz, 2H), 1.65-1.47 (m, 6H), 1.47-1.34 (m, 3H), 1.34-1.11 (m,6H), 1.06 (s, 3H), 1.00 (s, 3H), 0.94 (s, 6H), 0.93 (s, 3H).

Section 6. F-Benzoic Acid Derivatives Example A1 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoicacid

Step 1. Preparation of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-benzyl9-(3-fluoro-4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate

A suspension of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-benzyl5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-9-(trifluoromethylsulfonyloxy)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate(4.0 g, 5.91 mmol), 3-fluoro-4-(methoxycarbonyl)phenylboronic acid(1.287 g, 6.50 mmol), sodium carbonate monohydrate (2.198 g, 17.73mmol), and Pd(PPh₃)₄ (0.205 g, 0.177 mmol) in 1,4-dioxane (24 mL) andwater (6 mL) was flushed with N₂ and the mixture was heated to reflux.After 2 h of heating, the mixture was cooled to rt. The mixture wasdiluted with water (40 mL) and was extracted with dichloromethane (3×40mL). The combined organic layers were dried with Na₂SO₄. The dryingagent was removed by filtration and the filtrate was concentrated underreduced pressure. The residue was dissolved in DCM and was filteredthrough a pad of celite and silica gel, washing with a 25% EtOAc inhexanes solution. The filtrate was concentrated under reduced pressureto give the title compound (3.59 g, 5.27 mmol, 89% yield) as a dark greyfoam. The crude product was used in the next step with no additionalpurification. ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.80 (1H, t, J=7.8Hz), 7.29-7.42 (5H, m), 6.96 (1H, d, J=7.9 Hz), 6.91 (1H, d, J=11.9 Hz),5.28-5.33 (1H, m), 5.16 (1H, d, J=12.5 Hz), 5.09 (1H, d, J=12.2 Hz),4.73 (1H, s), 4.59 (1H, br. s.), 3.92 (3H, s), 3.03 (1H, td, J=10.8, 4.7Hz), 2.20-2.33 (2H, m), 2.09 (1H, dd, J=17.1, 6.4 Hz), 1.81-1.97 (2H,m), 1.68 (3H, s), 0.96 (3H, s), 0.92 (3H, s), 0.92 (3H, s), 0.91 (3H,s), 0.81 (3H, s), 0.79-1.75 (17H, m).

Step 2. Preparation of(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(3-fluoro-4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylicacid

To a solution of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-benzyl9-(3-fluoro-4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate(3.59 g, 5.27 mmol) in DCE (25 mL) was added TEA (1.176 mL, 8.44 mmol),t-butyldimethylsilane (1.749 mL, 10.54 mmol), and palladium(II) acetate(0.118 g, 0.527 mmol). The mixture was flushed with N₂ and heated to 60°C. for 1 h. The mixture was cooled to rt and was filtered through a plugof celite and silica gel (washed with 25% EtOAc in hexanes). Thefiltrate was concentrated under reduced pressure. The residue wasdiluted with 25 mL of dioxane and TBAF (75% in water) (2.76 g, 7.91mmol) was added. The mixture was stirred for 30 minutes at rt then wasdiluted with 50 mL of 1N HCl. The solids that formed were collected byfiltration and were washed with water to give the title compound (2.95g, 4.99 mmol, 95% yield) as a white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.83 (1H, t, J=7.9 Hz), 6.90-7.00 (2H, m), 5.34 (1H,dd, J=6.1, 1.6 Hz), 4.77 (1H, d, J=2.0 Hz), 4.64 (1H, s), 3.94 (3H, s),3.04 (1H, td, J=10.7, 4.8 Hz), 2.24-2.34 (2H, m), 2.13 (1H, dd, J=17.3,6.3 Hz), 1.96-2.06 (2H, m), 1.72 (3H, s), 1.03 (3H, s), 1.02 (3H, s),0.98 (3H, s), 0.93-0.96 (6H, m), 0.91-1.80 (17H, m).

Step 3. Preparation of methyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(3-fluoro-4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylicacid (2.95 g, 4.99 mmol) in toluene (50 mL) and TEA (1.39 mL, 9.99 mmol)was added diphenyl phosphorazidate (1.614 mL, 7.49 mmol) and the mixturewas heated to reflux. After 3 h, the reaction mixture was concentratedunder reduced pressure, was adsorbed to silica gel, and was purified byflash chromatography using a 0-10% EtOAc in hexanes gradient to give thetitle compound as a white solid. The material was used in the next stepwith no additional purification. ¹H NMR (500 MHz, Chloroform-d) δ ppm7.81 (1H, t, J=7.8 Hz), 6.96 (1H, dd, J=7.9, 1.5 Hz), 6.92 (1H, dd,J=11.9, 1.5 Hz), 5.31 (1H, dd, J=6.3, 1.7 Hz), 4.75 (1H, s), 4.64 (1H,s), 3.92 (3H, s), 2.55 (1H, td, J=10.8, 5.8 Hz), 2.05-2.16 (2H, m),1.76-1.92 (4H, m), 1.68 (3H, s), 1.09-1.11 (3H, m), 0.97 (3H, s), 0.96(3H, s), 0.94 (3H, s), 0.92 (3H, s), 0.88-1.75 (16H, m).

Step 4. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3α-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoatedihydrochloride

To a solution of crude methyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(2.93 g, 4.99 mmol) in THF (35 mL) was added 12N HCl (10 mL, 121 mmol).After stirring the mixture for 24 h, the mixture was diluted with water(100 mL) until solids precipitated. The solids were collected byfiltration and were washed with water to afford the title compound (2.75g, 4.33 mmol, 87% yield), as an off-white solid that was used in thenext step with no additional purification. LCMS: m/e 562 (M+H)⁺, 1.96min (method 2).

Step 5. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoicacid

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoate(100 mg, 0.178 mmol) in 1,4-dioxane (2 mL) was added 1N NaOH (0.890 mL,0.890 mmol). Solids formed upon the addition of the NaOH. The mixturewas heated to 60° C. After 20 minutes of heating, the mixture stillcontained solids. The mixture was further diluted with 1 mL of MeOH and2 mL of dioxane then was heated to 60° C. overnight (solids did notcompletely dissolve).

After 21 h of heating, the mixture was cooled to rt. The mixture wasdiluted with 3 mL of water and the solids that remained were collectedby filtration and were washed with water then with ether to give4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoicacid (67 mg, 0.113 mmol, 63.2% yield) as a white solid. LCMS: m/e 548.4(M+H)⁺, 2.29 min (method 11).

Example A2 Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxido-4-thiomorpholinyl)ethyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]-2-fluoro-,HCl

Step 1. Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxido-4-thiomorpholinyl)ethyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]-2-fluoro-,methyl ester

To a sealable flask containing methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoate,HCl (319 mg, 0.533 mmol) was added thiomorpholine, 4-(2-chloroethyl)-,1,1-dioxide, HCl (385 mg, 1.644 mmol), potassium iodide (240 mg, 1.446mmol), and phosphoric acid, potassium salt (500 mg, 2.356 mmol). Themixture was diluted with acetonitrile (10 mL), was flushed with N₂, thenthe vial was sealed and heated to 120° C. for 115 h. The mixture wascooled to rt and was directly purified by flash chromatography using a0-5% MeOH in DCM gradient. The fractions containing the expected productwere combined and were concentrated under reduced pressure to give thetitle compound (0.308 g, 0.426 mmol, 80% yield) as an off white foam.LCMS: m/e 723.5 (M+H)⁺, 1.94 min (method 2).

Step 2. Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxido-4-thiomorpholinyl)ethyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]-2-fluoro-,HCl

To a solution of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxido-4-thiomorpholinyl)ethyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]-2-fluoro-,methyl ester (0.308 g, 0.426 mmol) in 1,4-dioxane (5 mL) was added 1Nsodium hydroxide (2.130 mL, 2.130 mmol). The mixture was heated to 70°C. for 18 h then was cooled to rt. To the mixture was added 1N HClslowly until solids began to form. The solids were collected byfiltration and were washed with water to give benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxido-4-thiomorpholinyl)ethyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]-2-fluoro-,HCl as an off-white solid (0.295 g, 0.396 mmol, 93% yield). LCMS: m/e709.5 (M+H)⁺, 1.66 min (method 2). ¹H NMR (500 MHz, Acetic acid d4) δppm 7.96 (1H, t, J=7.8 Hz), 7.09 (1H, dd, J=7.9, 1.5 Hz), 7.03 (1H, d,J=11.9 Hz), 5.43 (1H, d, J=4.6 Hz), 4.84 (1H, s), 4.74 (1H, s),3.43-3.49 (1H, m), 3.02-3.36 (11H, m), 2.91-3.00 (1H, m), 1.77 (3H, s),1.30 (3H, s), 1.15 (3H, s), 1.10 (3H, s), 1.04 (3H, s), 1.01 (3H, s),0.98-2.34 (22H, m).

Example A3 Preparation of2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a sealable flask containing methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoate,HCl (0.1 g, 0.167 mmol) was added 4-(2-chloroethyl)morpholine, HCl(0.093 g, 0.501 mmol), phosphoric acid, potassium salt (0.156 g, 0.735mmol) and potassium iodide (0.075 g, 0.451 mmol). The mixture wasdiluted with acetonitrile (3 mL), was flushed with N₂, and the vial wassealed and heated to 120° C. After heating the mixture for 16 h, the itwas cooled to rt. The crude product was adsorbed to silica gel then waspurified by flash chromatography using a Thomson 12 g silica gel columnand a 0-5% MeOH in DCM gradient. The fractions containing the expectedproduct were combined and concentrated under reduced pressure to givemethyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(77 mg, 0.114 mmol, 68.3% yield) as an off-white foam. LCMS: m/e 675.5(M+H)⁺, 1.91 min (method 2).

Step 2. Preparation of2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a solution of methyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.075 g, 0.111 mmol) in 1,4-dioxane (1 mL) was added NaOH (1M) (0.5 mL,0.500 mmol). The mixture was heated to 75° C. for 15 h then was cooledto rt. The mixture was purified by prep HPLC. The fractions containingthe expected product were combined and concentrated under reducedpressure to give2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (30 mg, 0.043 mmol, 38.8% yield) as a white solid. LCMS: m/e 661.5(M+H)⁺, 1.66 min (method 2). ¹H NMR (500 MHz, Acetic Acid d₄) δ ppm 7.96(1H, t, J=7.9 Hz), 7.09 (1H, dd, J=8.2, 1.2 Hz), 7.03 (1H, d, J=11.6Hz), 5.42 (1H, d, J=4.6 Hz), 4.86 (1H, s), 4.74 (1H, s), 3.89-3.99 (4H,m), 3.53-3.69 (4H, m), 3.29 (4H, br. s.), 2.81-2.90 (1H, m), 1.77 (3H,s), 1.23 (3H, s), 1.13 (3H, s), 1.08 (3H, s), 1.04 (3H, s), 1.01 (3H,s), 0.85-2.26 (22H, m).

Example A4 Preparation of2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(2-oxopyrrolidin-1-yl)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(2-oxopyrrolidin-1-yl)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a vial containing N-(2-hydroxyethyl)-2-pyrrolidone (0.5 mL, 4.42mmol) was added DMAP (0.054 g, 0.442 mmol) and TEA (0.925 mL, 6.64mmol). The mixture was diluted with d-chloroform (10 mL) and was cooledto 0° C. then triflic anhydride (0.822 mL, 4.87 mmol) was added slowly.The mixture turned a dark red color as the anhydride was added. Themixture was warmed to rt and stirred for 45 minutes. The 0.442 Msolution was used directly as the alkylating agent for the followingreaction.

To a sealable flask containing methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoate(50 mg, 0.089 mmol) was added potassium iodide (39.9 mg, 0.240 mmol) andphosphoric acid, potassium salt (83 mg, 0.392 mmol). The mixture wasdiluted with acetonitrile (1 mL) and the crude alkylating solutiondescribed above (1.007 mL, 0.445 mmol) was added. The mixture wasflushed with N₂ and the vial was sealed and heated to 120° C. After 15.5h of heating, the mixture was cooled to rt. An additional 0.5 mL of thecrude alkylating solution was added and the mixture was again heated to120° C. After 70.25 h, the mixture was cooled to rt. The mixture wasadsorbed to silica gel and was purified by flash chromatography using a0-5% MeOH in DCM gradient and a Thomson 12 g silica gel column. Thefractions containing the expected product were combined and wereconcentrated under reduced pressure to give methyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(2-oxopyrrolidin-1-yl)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(25 mg, 0.037 mmol, 41.7% yield) as a yellow film. LCMS: m/e 673.5(M+H)⁺, 2.03 min (method 2).

Step 2. Preparation of2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(2-oxopyrrolidin-1-yl)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a solution of methyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(2-oxopyrrolidin-1-yl)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.025 g, 0.037 mmol) in 1,4-dioxane (1 mL) was added NaOH (1N) (0.5 mL,0.500 mmol). The mixture was warmed to 60° C. for 15. 5 h then wascooled to rt and purified by prep HPLC. The fractions containing theexpected product were combined and concentrated under reduced pressureto give2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(2-oxopyrrolidin-1-yl)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (11 mg, 0.016 mmol, 42.2% yield) as a white solid. LCMS: m/e 659.5(M+H)⁺, 1.77 min (method 2). ¹H NMR (500 MHz, CHLOROFORM-d) δ 7.82 (t,J=6.9 Hz, 1H), 6.91 (d, J=6.1 Hz, 1H), 6.86 (d, J=11.9 Hz, 1H), 5.27 (d,J=4.6 Hz, 1H), 4.71 (s, 1H), 4.58 (s, 1H), 3.54-3.43 (m, 3H), 3.39-3.31(m, 1H), 1.68 (s, 3H), 1.06 (s, 3H), 0.96 (s, 3H), 0.93 (s, 3H), 0.90(s, 3H), 0.90 (s, 3H), 2.75-0.66 (m, 29H).

Example A5 Preparation of2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(2-oxopyrrolidin-1-yl)propylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(2-oxopyrrolidin-1-yl)propylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a vial containing 1-(3-hydroxypropyl)-2-pyrrolidone (0.5 mL, 3.84mmol) was added DMAP (0.047 g, 0.384 mmol) and TEA (0.803 mL, 5.76mmol). The mixture was diluted with d-chloroform (10 mL) and was cooledto 0° C. To the cooled solution was added trifluoromethanesulfonicanhydride (0.714 mL, 4.23 mmol) slowly. The mixture turned dark red asthe anhydride was added. The mixture was slowly warmed to rt as the icebath melted. After 1 h of stirring at rt, ¹HNMR showed no startingmaterial remained. The crude reaction mixture was used directly in thefollowing reaction with no purification.

To a sealable flask containing methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoate(50 mg, 0.089 mmol) was added potassium iodide (39.9 mg, 0.240 mmol) andphosphoric acid, potassium salt (83 mg, 0.392 mmol). The mixture wasdiluted with acetonitrile (1 mL) and 3-(2-oxopyrrolidin-1-yl)propyltrifluoromethanesulfonate (the crude solution prepared above) (1.0 mL,0.384 mmol) was added. The mixture was flushed with N₂, then the vialwas sealed and heated to 120° C. After 15.5 h of heating, the mixturewas cooled to rt. An additional 0.5 mL of the above crude solutioncontaining the triflate was added and the mixture was again heated to120° C. After heating the mixture for an additional 70.25 h, the mixturewas cooled to rt. The mixture was adsorbed to silica gel and waspurified by flash chromatography using a 0-5% MeOH in DCM gradient and aThomson 12 g silica gel column. The fractions containing the expectedproduct were combined and concentrated under reduced pressure to givemethyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(2-oxopyrrolidin-1-yl)propylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(16 mg, 0.023 mmol, 26.2% yield) as a yellow film. LCMS: m/e 687.5(M+H)⁺, 2.04 min (method 2).

Step 2. Preparation of2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(2-oxopyrrolidin-1-yl)propylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

To a solution of methyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(2-oxopyrrolidin-1-yl)propylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(16 mg, 0.023 mmol) in 1,4-dioxane (1 mL) was added NaOH (1N) (0.25 mL,0.250 mmol). The mixture was heated to 60° C. overnight for 15.25 h thenwas cooled to rt. The mixture was directly loaded onto the prep HPLC forpurification. The fractions containing the expected product werecombined and concentrated under reduced pressure to give2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(2-oxopyrrolidin-1-yl)propylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (6 mg, 8.02 mmol, 34.5% yield) as a clear, colorless film. LCMS:m/e 673.5 (M+H)⁺, 1.75 min (method 2). ¹H NMR (500 MHz, Acetic acid d₄)δ 7.96 (t, J=7.9 Hz, 1H), 7.09 (dd, J=7.9, 1.2 Hz, 1H), 7.03 (d, J=11.9Hz, 1H), 5.42 (d, J=4.6 Hz, 1H), 4.86 (s, 1H), 4.74 (s, 1H), 3.58-3.40(m, 4H), 3.26-3.16 (m, 2H), 2.94-2.85 (m, 1H), 2.56-2.48 (m, 2H), 1.76(s, 3H), 1.22 (s, 3H), 1.13 (s, 3H), 1.08 (s, 3H), 1.04 (s, 3H), 1.01(s, 3H), 2.29-0.85 (m, 26H).

Example A6 Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[3-(1,1-dioxido-4-thiomorpholinyl)propyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]-2-fluoro-

Step 1. Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[3-(1,1-dioxido-4-thiomorpholinyl)propyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]-2-fluoro-,methyl ester

To a vial containing N-(3-hydroxypropyl)thiomorpholine-1,1-dioxide (0.15g, 0.776 mmol) was added DMAP (9.48 mg, 0.078 mmol) and TEA (0.162 mL,1.164 mmol). The mixture was diluted with d-chloroform (2 mL) and wascooled to 0° C. To the cooled solution was addedtrifluoromethanesulfonic anhydride (0.144 mL, 0.854 mmol) slowly. Themixture turned orange as the anhydride was added and became a thick gelwhich did not stir well. After 2 h the mixture was diluted with anadditional 1 mL of d-chloroform and was used directly in the followingreaction as the crude reaction mixture.

To a sealable flask containing methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoate(50 mg, 0.089 mmol) was added potassium iodide (39.9 mg, 0.240 mmol) andphosphoric acid, potassium salt (83 mg, 0.392 mmol). The mixture wasdiluted with acetonitrile (1 mL) and a solution of the crude mixturefrom the reaction above (1.718 mL, 0.445 mmol) was added. The mixturewas flushed with N₂ and the vial was sealed and heated to 120° C. Afterstirring the mixture for 66 h it was cooled to rt. The mixture wasadsorbed to silica gel and was purified by flash chromatography using a12 g Thomson silica gel column and a 0-5% MeOH in DCM gradient. Thefractions containing the expected product were combined and concentratedunder reduced pressure to give benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[3-(1,1-dioxido-4-thiomorpholinyl)propyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]-2-fluoro-,methyl ester (43 mg, 0.058 mmol, 65.6% yield) as a yellow film. LCMS:m/e 737.5 (M+H)⁺, 1.88 min (method 2).

Step 2. Preparation of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[3-(1,1-dioxido-4-thiomorpholinyl)propyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]-2-fluoro-

To a solution of benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[3-(1,1-dioxido-4-thiomorpholinyl)propyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]-2-fluoro-,methyl ester (0.043 g, 0.058 mmol) in 1,4-dioxane (1 mL) was added NaOH(1M) (0.5 ml, 0.500 mmol). The mixture was heated to 60° C. for 15.25 hand was cooled to rt. The mixture was directly loaded onto the prep HPLCfor purification. The fractions containing the expected product werecombined and concentrated under reduced pressure to give benzoic acid,4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[3-(1,1-dioxido-4-thiomorpholinyl)propyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]-2-fluoro-(13.2 mg, 0.017 mmol, 29.4% yield) as a white solid. LCMS: m/e 723.5(M+H)⁺, 1.62 min (method 2). ¹H NMR (400 MHz, Acetic acid d4) δ 7.92 (t,J=7.9 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.98 (d, J=11.8 Hz, 1H), 5.38 (d,J=4.8 Hz, 1H), 4.82 (s, 1H), 4.70 (s, 1H), 3.71 (br. s., 4H), 3.48 (br.s., 4H), 3.25 (t, J=7.5 Hz, 4H), 2.82 (br. s., 1H), 2.46-2.30 (m, 2H),1.72 (s, 3H), 1.16 (s, 3H), 1.08 (s, 3H), 1.03 (s, 3H), 0.99 (s, 3H),0.97 (s, 3H), 2.24-0.82 (m, 22H).

Example A7 Preparation of2-fluoro-4-41R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a sealable flask containing methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoatehydrochloride (0.1 g, 0.167 mmol) was added 4-(2-chloroethyl)morpholinehydrochloride (0.093 g, 0.501 mmol), phosphoric acid, potassium salt(0.156 g, 0.735 mmol) and potassium iodide (0.075 g, 0.451 mmol). Themixture was diluted with acetonitrile (3 mL), was flushed with nitrogen,then the vial was sealed and heated to 120° C. After heating the mixturefor 16 h, the mixture was cooled to rt. The crude product was adsorbedto silica gel then was purified by flash chromatography using a Thomson12 g silica gel column and a 0-5% methanol in dichloromethane gradient.The fractions containing the expected product were combined andconcentrated under reduced pressure to give methyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(77 mg, 0.114 mmol, 68.3% yield) as an off-white foam. LCMS: m/e 675.5(M+H)⁺, 1.91 min (method 2).

Step 2. To a solution of methyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

(0.075 g, 0.111 mmol) in 1,4-Dioxane (1 mL) was added NaOH (1M) (0.5 mL,0.500 mmol). The mixture was heated to 75° C. for 15 h then was cooledto rt. The mixture was acidified with 1N HCl (3 mL) and was concentratedunder reduced pressure. The residue was diluted with 15 mL of water andthe solids that remained were collected by filtration and were washedwith water then with ether. The compound was dissolved in DMF andmethanol and was purified by prep HPLC. Fractions containing theexpected product were combined and concentrated under reduced pressureto give2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (30 mg, 0.043 mmol, 38.8% yield) as a white solid. LCMS: m/e 661.5(M+H)⁺, 1.67 min (method 2). ¹H NMR (500 MHz, Acetic acid d₄) ppm 7.96(1H, t, J=7.9 Hz), 7.09 (1H, dd, J=8.2, 1.2 Hz), 7.03 (1H, d, J=11.6Hz), 5.42 (1H, d, J=4.6 Hz), 4.86 (1H, s), 4.74 (1H, s), 3.89-3.99 (4

H, m), 3.53-3.69 (4H, m), 3.29 (4H, br. s.), 2.81-2.90 (1H, m), 1.77(3H, s), 1.23 (3H, s), 1.13 (3H, s), 1.08 (3H, s), 1.04 (3H, s), 1.01(3H, s), 0.85-2.26 (22H, m).

Example A8 Preparation of2-fluoro-4-41R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-β2-(4-(methylsulfonyl)piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-hydroxyethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a sealable flask containing methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoate,HCl (1.0 g, 1.671 mmol) was added potassium iodide (0.694 g, 4.18 mmol),phosphoric acid, potassium salt (1.774 g, 8.36 mmol) and 2-bromoethanol(0.475 mL, 6.69 mmol). The mixture was diluted with acetonitrile (15 mL)and the vial was sealed and heated to 120° C. for 21 h then was cooledto rt and was diluted with water (50 mL). The solids were collected byfiltration then were washed with water. The solids were purified byflash chromatography in silica gel using a 0-5% methanol indichloromethane gradient with 0.1% ammonium hydroxide added to themixture The fractions containing the expected product were combined andwere concentrated under reduced pressure. The product was repurified asecond time using a 0-20% EtOAc in hexanes gradient with 0.1% TEA addedto the mixture. The fractions containing the product combined and wereconcentrated under reduced pressure to give methyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-hydroxyethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.135 g, 0.223 mmol, 13% yield) as an off-white solid. LCMS: m/e 606.7(M+H)⁺, 2.02 min (method 2).

Step 2. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-chloroethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoate,HCl

To a flask containing methyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-hydroxyethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.135 g, 0.223 mmol) was added thionyl chloride (2.5 ml, 34.3 mmol).The clear, colorless solution was stirred at rt for 2.5 h the reactionwas carefully quenched with water (20 mL) and the solids that formedwere collected by filtration and were washed with water. The expectedproduct, methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-chloroethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoate,HCl (0.173 g, 0.262 mmol, 117% yield), was isolated as an off-whitesolid which was directly used in the next step with no additionalpurification. LCMS: m/e 624.6 (M+H)⁺, 2.42 min (method 11).

Step 3. Preparation of methyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a suspension of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-chloroethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoate,HCl (0.147 g, 0.223 mmol) in DMSO (2 mL) was added1-methanesulfonyl-piperazine (0.073 g, 0.446 mmol) and Hunig's Base(0.195 mL, 1.115 mmol). Upon addition of the base, the solids dissolved.The solution was heated to 120° C. for 2 h then was cooled to rt, wasdiluted with water (20 mL) and was extracted with ethyl acetate (3×20mL). The combined organic layers were washed with water (2×30 mL) thenwith brine (20 mL), then were dried over magnesium sulfate. The dryingagent was removed by filtration and the filtrate was concentrated underreduced pressure. The residue was purified by flash chromatography insilica gel using a 0-50% ethyl acetate in hexanes gradient with 0.1%triethyl amine added to the mixture. The fractions containing theexpected product were combined and were concentrated under reducedpressure to give methyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.056 g, 0.074 mmol, 33.4% yield) as an off-white solid. LCMS: m/e752.7 (M+H)⁺, 1.95 min (method 2).

Step 4. To a solution of methyl2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(0.056 g, 0.074 mmol) in 1,4-dioxane (2 mL) was added NaOH (1N) (0.372mL, 0.372 mmol). The mixture was heated to 60° C. for 6.5 h then wascooled to rt. The mixture was diluted with methanol and 1,4-dioxane, wasfiltered through a plug of glass wool and was purified by prep HPLC. Thefractions containing the expected product were combined and wereconcentrated under reduced pressure to give2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (30.1 mg, 0.039 mmol, 52.0% yield) as a white solid. LCMS: m/e738.6 (M+H)⁺, 1.66 min (method 2). ¹H NMR (400 MHz, Acetic acid d₄)δ7.92 (t, J=7.9 Hz, 1H), 7.04 (dd, J=8.0, 1.5 Hz, 1H), 7.01-6.96 (m,1H), 5.38 (d, J=5.0 Hz, 1H), 4.81 (s, 1H), 4.70 (s, 1H), 3.59-3.25 (m,8H), 3.15 (br. s., 4H), 2.90 (s, 3H), 2.94-2.81 (m, 1H), 1.72 (s, 3H),1.21 (s, 3H), 1.09 (s, 3H), 1.04 (s, 3H), 0.99 (s, 3H), 0.97 (s, 3H),2.23-0.83 (m, 22H).

Section B. Amines (Continued) Example B1 Preparation of5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)thiophene-2-carboxylicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoicacid using 5-(methoxycarbonyl)thiophen-2-ylboronic acid as the couplingreagent in Step 1. The product was isolated as a white solid (2.7 mg,44%). LCMS: m/e 536.30 (M+H)⁺, 2.25 min (method 10). ¹H NMR (500 MHz,Acetic) δ 7.77 (d, J=4.0 Hz, 1H), 6.98 (d, J=3.7 Hz, 1H), 5.87 (d, J=4.3Hz, 1H), 4.88 (s, 1H), 4.75 (s, 1H), 2.79 (td, J=10.5, 6.7 Hz, 1H),2.35-2.13 (m, 4H), 1.98-1.85 (m, 4H), 1.83-1.07 (m, 14H), 1.77 (s, 3H),1.19 (s, 3H), 1.14 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H).

Example B2 Preparation of4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of(1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-1-isopropyl-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysene-3a-carboxylicacid

A mixture of palladium on carbon (67.4 mg, 0.063 mmol) and(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-benzyl9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate(140 mg, 0.211 mmol) in methanol (2 mL) was stirred at 20° C. underhydrogen at 1 atmosphere of pressure for 20 hours. The reaction mixturewas filtered through a celite pad to remove Pd/C. The filtrates wereconcentrated under reduced pressure to provide the title compound as awhite solid (100 mg, 82%). LCMS: m/e 577.33 (M+H)⁺, 3.22 min (method10).

Step 2. Preparation of methyl4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-amino-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

A mixture of(1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-1-isopropyl-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysene-3a-carboxylicacid (100 mg, 0.173 mmol), diphenyl phosphorazidate (0.056 mL, 0.260mmol) and triethylamine (0.072 mL, 0.520 mmol) in toluene (4 mL) wasrefluxed for 18 hours. TLC indicated the consumption of startingmaterial and the formation of desired product. The mixture was cooled toroom temperature, filtered through a silica gel pad and the filtrateswere concentrated under reduced pressure to produce the desiredintermediate as colorless oil. To this intermediate (70 mg, 0.122 mmol)in THF (4 mL) was added HCl (0.037 mL, 1.220 mmol). The reaction mixturewas stirred for 18 hours at room temperature. The reaction mixture waspurified by chromatography in silica gel with 20-70% ethylacetate/hexanes to provide the title compound as white solid (50 mg,50%). LCMS: m/e 548.49 (M+H)⁺, 2.58 min (method 11).

Step 3. Preparation of methyl4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

A mixture of methyl4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-amino-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(50 mg, 0.091 mmol), 4-(2-chloroethyl)thiomorpholine 1,1-dioxide (54.1mg, 0.274 mmol), potassium phosphate (77 mg, 0.365 mmol) and potassiumiodide (36.4 mg, 0.219 mmol) in acetonitrile (2 mL) was heated up at120° C. for 20 hours. The reaction mixture was quenched with distilledwater (5 mL), extracted with dichloromethane (3×5 mL), the organicphases were combined, dried over sodium sulfate, filtered andconcentrated under reduced pressure to provide the crude product as ayellow solid (40 mg, 62%). LCMS: m/e 709.53 (M+H)⁺, 2.46 min (method11).

Step 4. Preparation of4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

A mixture of methyl4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(40 mg, 0.056 mmol) and sodium hydroxide (0.564 mL, 0.564 mmol) indioxane (1 mL) was heated up at 80° C. for 3 hours. The reaction mixturewas filtered and purified by HPLC to provide the title compound as whitesolid (30 mg, 73%). LCMS: m/e 695.46 (M+H)⁺, 2.55 min (method 10). ¹HNMR (500 MHz, Acetic) δ 8.02 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H),3.44-3.36 (m, 1H), 3.35-3.21 (m, 6H), 3.19-2.99 (m, 5H), 2.50 (dd,J=13.0, 2.9 Hz, 1H), 2.34-1.01 (m, 26H), 1.28 (s, 3H), 1.13 (s, 3H),1.10 (s, 3H), 0.93 (d, J=6.7 Hz, 3H), 0.85 (d, J=6.7 Hz, 3H), 0.84 (s,3H), 0.80 (s, 3H).

Example B3 Preparation of4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-amino-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoicacid using methyl4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-amino-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoateas the starting material in Step 5. The product was isolated as a whitesolid (12 mg, 47%). LCMS: m/e 532.43 (M−H)⁻, 2.37 min (method 10). ¹HNMR (500 MHz, METHANOL-d₄) δ 7.84 (d, J=8.2 Hz, 2H), 7.19 (d, J=8.2 Hz,2H), 2.42 (dd, J=13.0, 2.9 Hz, 1H), 2.18 (qd, J=13.3, 3.1 Hz, 1H),2.07-1.24 (m, 25H), 1.16 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H), 0.93 (d,J=6.7 Hz, 3H), 0.83 (d, J=6.7 Hz, 3H), 0.79 (s, 3H), 0.74 (s, 3H).

Example B4 Preparation of4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a#2-morpholinoethyl)amino)icosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 4-(2-chloroethyl)morpholine as the alkylating reagent in Step3. The product was isolated as a colorless oil (4 mg, 39%). LCMS: m/e647.58 (M+H)⁺, 2.35 min (method 11). ¹H NMR (500 MHz, Acetic) δ 8.02 (d,J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 3.94 (d, J=3.7 Hz, 4H), 3.73-3.44(m, 4H), 3.27 (br. s., 4H), 2.50 (d, J=10.4 Hz, 1H), 2.32-1.01 (m, 26H),1.21 (s, 3H), 1.12 (s, 3H), 1.08 (s, 3H), 0.93 (d, J=6.7 Hz, 3H), 0.86(d, J=6.7 Hz, 3H), 0.83 (s, 3H), 0.79 (s, 3H).

Example B5 Preparation of4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-((2-(dimethylamino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 2-chloro-N,N-dimethylethanamine as the alkylating reagent inStep 3. The product was isolated as a colorless oil (0.9 mg, 37%). LCMS:m/e 605.56 (M+H)⁺, 2.35 min (method 11). ¹H NMR (500 MHz, Acetic) δ 8.02(d, J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 3.89-3.72 (m, 2H), 3.70-3.55(m, 1H), 3.07-2.91 (m, 1H), 3.00 (s, 6H), 2.60-2.40 (m, 1H), 2.34-1.04(m, 26H), 1.18 (s, 3H), 1.12 (s, 3H), 1.07 (s, 3H), 0.93 (d, J=6.7 Hz,3H), 0.86 (d, J=6.7 Hz, 3H), 0.83 (s, 3H), 0.79 (s, 3H).

Example B6 Preparation of4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-(bis(2-(dimethylamino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was obtained as a side product in the preparation4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-((2-(dimethylamino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid. The product was isolated as a colorless oil (0.7 mg, 26%). LCMS:m/e 676.63 (M+H)⁺, 2.33 min (method 11). ¹H NMR (500 MHz, Acetic) δ 8.02(d, J=8.2 Hz, 2H), 7.35 (d, J=8.2 Hz, 2H), 4.33-4.09 (m, 4H), 3.85 (br.s., 3H), 3.73 (br. s., 1H), 3.40 (s, 6H), 3.01 (s, 6H), 2.50 (d, J=14.0Hz, 1H), 2.37-1.04 (m, 26H), 1.17 (s, 3H), 1.12 (s, 3H), 1.07 (s, 3H),0.93 (d, J=6.7 Hz, 3H), 0.87 (d, J=6.7 Hz, 3H), 0.8 s (s, 3H), 0.79 (s,3H).

Example B7A and B7B Preparation of(2S,3S,4S,5R,6R)-6-((4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylicacid

Step 1. Preparation of (2S,3S,4S,5R,6R)-benzyl3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylate

To a solution of(2S,3S,4S,5R,6R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylicacid (1 g, 5.15 mmol) and TBAF in THF (6.18 mL, 6.18 mmol) in DMF (7 mL)was slowly added (bromomethyl)benzene (0.925 g, 5.41 mmol) at 0° C. Theclear solution was warmed up to room temperature slowly and let it stirfor 17 hours. TLC indicated the reaction was completed (20%iPrOH/CH₂Cl₂). The solvent was removed and the reaction residue waspurified by silica gel chromatography with 10-20% iPrOH/CH₂Cl₂ toprovide the desired product as a colorless oil (950 mg, 65%). LCMS: m/e283.31 (M−H)⁻, 2.55 min (method 10).

Step 2. Preparation of (2S,3S,4S,5R,6R)-benzyl6-((4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

A mixture of (2S,3S,4S,5R)-benzyl3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylate (61.7 mg, 0.217mmol),4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (100 mg, 0.145 mmol), HATU (88 mg, 0.232 mmol) andN-methylmorpholine (0.048 mL, 0.434 mmol) in dioxane (3 mL) was stirredovernight at room temperature. The reaction mixture was filtered, theclear solution was purified by prep HPLC withacetonitrile/water/ammonium acetate to provide the desired product aswhite solid (20 mg, 14%). LCMS: m/e 957.7 (M+H)⁺, 2.36 min (method 6).¹H NMR (500 MHz, Acetic) δ 8.05 (d, J=8.2 Hz, 2H), 7.58-7.14 (m, 7H),5.95 (d, J=7.6 Hz, 1H), 5.38 (d, J=4.6 Hz, 1H), 5.26 (s, 2H), 4.84 (s,1H), 4.74 (s, 1H), 4.30 (d, J=9.5 Hz, 1H), 4.05-3.78 (m, 3H), 3.46 (d,J=11.9 Hz, 1H), 3.38-3.22 (m, 6H), 3.20-3.11 (m, 3H), 3.07 (br. s., 2H),2.95 (dt, J=10.8, 5.5 Hz, 1H), 2.42-1.01 (m, 22H), 1.77 (s, 3H), 1.30(s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H).

Step 3. Preparation of(2S,3S,4S,5R,6R)-6-((4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylicacid

A mixture of (2S,3S,4S,5R,6R)-benzyl6-((4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate(8 mg, 8.36 mmol), tert-butyldimethylsilane (1.943 mg, 0.017 mmol),palladium acetate (3.75 mg, 0.017 mmol) and triethylamine (5.82 μl,0.042 mmol) in dichloroethane (1 mL) was heated up at 60° C. for 2hours. The reaction mixture was cooled to room temperature, filtered andthe filtrates were concentrated to provide the residue. To this residuein THF (1.0 mL) was added TBAF (10.93 mg, 0.042 mmol), the reactionmixture was stirred for 1 hours. The reaction mixture was then purifiedby prep. HPLC to provide the desired product as a colorless oil (4 mg,52%). LCMS: m/e 867.69 (M+H)⁺, 2.42 min (method 10). ¹H NMR (500 MHz,Acetic) δ 8.06 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H), 5.96 (d, J=7.9Hz, 1H), 5.37 (d, J=4.4 Hz, 1H), 4.84 (s, 1H), 4.74 (s, 1H), 4.40-4.16(m, 1H), 4.02-3.76 (m, 3H), 3.46 (d, J=12.3 Hz, 1H), 3.37-3.22 (m, 6H),3.20-3.11 (m, 3H), 3.07 (br. s., 2H), 3.00-2.82 (m, 1H), 2.37-1.03 (m,22H), 1.76 (s, 3H), 1.29 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.02 (s,3H), 0.99 (s, 3H).

Example B8 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1,1-dioxidotetrahydrothiophen-3-yl)amino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of 3-((2-hydroxyethyl)amino)tetrahydrothiophene1,1-dioxide

A mixture of 2-aminoethanol (310 mg, 5.08 mmol), triethylamine (514 mg,5.08 mmol) and 2,3-dihydrothiophene 1,1-dioxide (200 mg, 1.693 mmol) inethanol (3 mL) was heated up at 78° C. for 16 hours. TLC indicated thestarting material was consumed and desired product was formed (30%methanol/ethyl acetate). The reaction mixture was concentrated underreduced pressure, the residue was purified by silica gel chromatographywith 0-35% methanol/ethyl acetate to provide the title compound as acolorless oil (260 mg, 86%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 3.78-3.56(m, 3H), 3.38-3.21 (m, 2H), 3.14-3.00 (m, 1H), 2.94 (dd, J=13.3, 6.0 Hz,1H), 2.85-2.68 (m, 2H), 2.53-2.34 (m, 1H), 2.22-2.03 (m, 1H).

Step 2. Preparation of 3-((2-chloroethyl)amino)tetrahydrothiophene1,1-dioxide

A mixture of 3-((2-hydroxyethyl)amino)tetrahydrothiophene 1,1-dioxide(260 mg, 1.451 mmol) and sulfurous dichloride (863 mg, 7.25 mmol) indichloroethane (3 mL) was heated up at 78° C. for 3 hours. The mixturewas cooled to room temperature and concentrated under reduced pressureto provide the black oil. To this black oil was added THF (5 mL) anddichloromethane (5 mL), grey-white solid was observed. The solid wasfiltered and collected to provide the desired product as a grey solid(230 mg, 80%). LCMS: m/e 198.1 (M+H)⁺, 0.60 min (method 6).

Step 3. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1,1-dioxidotetrahydrothiophen-3-yl)amino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(50 mg, 0.092 mmol), 3-((2-chloroethyl)amino)tetrahydrothiophene1,1-dioxide (45.4 mg, 0.230 mmol), potassium phosphate (58.5 mg, 0.276mmol) and potassium iodide (30.5 mg, 0.184 mmol) in acetonitrile (1 mL)was heated up at 120° C. for 18 hours. The reaction mixture was quenchedwith distilled water (3 mL), extracted with dichloromethane (3×3 mL),the organic phases were combined, dried over sodium sulfate, filteredand concentrated under reduced pressure to provide the crude product asa white solid (40 mg, 62%). LCMS: m/e 705.48 (M+H)⁺, 2.44 min (method11).

Step 4. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1,1-dioxidotetrahydrothiophen-3-yl)amino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1,1-dioxidotetrahydrothiophen-3-yl)amino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(40 mg, 0.057 mmol) and sodium hydroxide (0.567 mL, 0.567 mmol) indioxane (1 mL) was heated up at 78° C. for 3 hours. The reaction mixturewas cooled to room temperature, filtered and the clear solution waspurified by HPLC to provide the title compound as a white solid (26 mg,63%). LCMS: m/e 691.46 (M+H)⁺, 2.24 min (method 11). ¹H NMR (500 MHz,Acetic) δ 8.04 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.37 (d, J=4.9Hz, 1H), 4.87 (s, 1H), 4.75 (s, 1H), 4.06 (quin, J=7.7 Hz, 1H),3.67-3.45 (m, 4H), 3.44-3.34 (m, 1H), 3.33-3.11 (m, 2H), 2.92-2.80 (m,1H), 2.77-2.59 (m, 1H), 2.42-2.29 (m, 1H), 2.26-1.02 (m, 23H), 1.77 (s,3H), 1.22 (s, 3H), 1.13 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H), 1.00 (s,3H).

Example B9 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1,1-dioxidotetrahydrothiophen-3-yl)amino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

A mixture of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(isopropylamino)-2-oxoethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid (15 mg, 0.024 mmol) and Pd/C (7.61 mg, 7.16 mmol) in methanol (1mL) and ethyl acetate (1.000 mL) was stirred for 12 hours at roomtemperature under hydrogen at 1 atmosphere of pressure. The reactionmixture was filtered and the solution was purified by HPLC to providethe title compound as a white solid (6 mg, 38%). LCMS: m/e 633.48(M+H)⁺, 2.62 min (method 10). ¹H NMR (500 MHz, Acetic) δ 8.02 (d, J=8.2Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 4.17 (d, J=15.6 Hz, 1H), 4.09 (quin,J=6.6 Hz, 1H), 3.82 (d, J=15.3 Hz, 1H), 2.50 (dd, J=13.1, 2.7 Hz, 1H),2.34-1.05 (m, 26H), 1.27 (s, 3H), 1.19 (s, 3H), 1.18 (s, 3H), 1.13 (s,3H), 1.08 (s, 3H), 0.94 (d, J=6.7 Hz, 3H), 0.86 (d, J=6.7 Hz, 3H), 0.84(s, 3H), 0.80 (s, 3H).

Example B10 Preparation of4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylamino)-2-oxoethyl)amino)icosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1,1-dioxidotetrahydrothiophen-3-yl)amino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylamino)-2-oxoethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid as the starting material. The product was isolated as a white solid(3 mg, 28%). LCMS: m/e 605.45 (M+H)⁺, 2.58 min (method 10). ¹H NMR (500MHz, Acetic) δ 8.02 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 4.22 (d,J=15.6 Hz, 1H), 3.85 (d, J=15.6 Hz, 1H), 2.87 (s, 3H), 2.50 (dd, J=13.1,2.4 Hz, 1H), 2.35-1.02 (m, 26H), 1.28 (s, 3H), 1.13 (s, 3H), 1.08 (s,3H), 0.95 (d, J=6.7 Hz, 3H), 0.87 (d, J=6.7 Hz, 3H), 0.84 (s, 3H), 0.80(s, 3H).

Example B11 Preparation of4-((1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a-((3-morpholinopropyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1,1-dioxidotetrahydrothiophen-3-yl)amino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((3-morpholinopropyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid as the starting material. The product was isolated as a white solid(5 mg, 40%). LCMS: m/e 659.55 (M+H)⁺, 2.86 min (method 10). ¹H NMR (500MHz, Acetic) δ 8.04 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.38 (d,J=4.6 Hz, 1H), 3.98 (br. s., 4H), 3.47-3.14 (m, 6H), 2.58-2.34 (m, 1H),2.30-1.04 (m, 27H), 1.21 (s, 3H), 1.11 (s, 3H), 1.11 (s, 3H), 1.02 (s,3H), 1.00 (s, 3H), 0.93 (d, J=6.7 Hz, 4H), 0.86 (d, J=6.7 Hz, 3H).

Example B12 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-carboxyethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-methoxy-3-oxopropyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(20 mg, 0.037 mmol), methyl acrylate (0.013 mL, 0.147 mmol) andtriethylamine (0.026 mL, 0.184 mmol) in ethanol (1 mL) was refluxed for5 hours. The reaction mixture was cooled to room temperature and thenconcentrated under reduced pressure to provide the desired product as ayellow oil (15 mg 65%). LCMS: m/e 630.43 (M+H)⁺, 3.81 min (method 10).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-carboxyethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-methoxy-3-oxopropyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(15 mg, 0.024 mmol) and sodium hydroxide (0.238 mL, 0.238 mmol) indioxane (1 mL) was heated up at 80° C. for 3 hours. The reaction mixturewas cooled to room temperature and then filtered, the clear solution waspurified by HPLC to provide the title compound as a white solid (5 mg,33%). LCMS: m/e 602.43 (M+H)⁺, 2.25 min (method 10). ¹H NMR (500 MHz,Acetic) δ 8.04 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.37 (d, J=4.9Hz, 1H), 4.86 (s, 1H), 4.74 (s, 1H), 3.39 (t, J=4.4 Hz, 2H), 3.17-3.02(m, 1H), 2.98-2.80 (m, 2H), 2.31-1.02 (m, 22H), 1.77 (s, 3H), 1.24 (s,3H), 1.14 (s, 3H), 1.09 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).

Example B13 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-hydroxyethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(1500 mg, 2.76 mmol), 2-bromoethanol (1034 mg, 8.27 mmol), potassiumphosphate (1756 mg, 8.27 mmol) and potassium iodide (916 mg, 5.52 mmol)in acetonitrile (10 mL) was heated up at 120° C. for 15 hours. Thereaction mixture was poured into distilled water (40 mL). The whiteprecipitate was filtered and washed with distilled water (100 mL). Thewhite solid was dried under vacuum to provide the desired product (1.4g, 86%). LCMS: m/e 588.5 (M+H)⁺, 2.40 min (method 11).

Step 2. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-chloroethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-hydroxyethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(1400 mg, 2.381 mmol) and thionyl chloride (1.738 mL, 23.81 mmol) indichloroethane (15 mL) was heated up at 60° C. for 2 hours. The reactionmixture was concentrated under reduced pressure to provide the desiredproduct as brown solid (1.3 g, 90%). LCMS: m/e 606.48 (M+H)⁺, 2.46 min(method 11).

Step 3. Preparation of tert-butyl4-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)amino)ethyl)piperazine-1-carboxylate

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-chloroethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(230 mg, 0.379 mmol), Hunig's Base (0.331 mL, 1.895 mmol) and tert-butylpiperazine-1-carboxylate (141 mg, 0.759 mmol) in DMSO (3 mL) was heatedup at 120° C. for 1 hour. The reaction mixture was quenched with water(10 mL), extracted with ethyl acetate (3×8 mL), the extracts werecombined, dried over sodium sulfate, filtered and concentrated underreduced pressure to provide the crude, the crude was purified by silicagel chromatography with 0-30% ethyl acetate/hexanes to provide thedesired product as a white solid (150 mg, 52%). LCMS: m/e 756.66 (M+H)⁺,2.50 min (method 11).

Step 4. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

A mixture of tert-butyl4-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)amino)ethyl)piperazine-1-carboxylate(4 mg, 5.29 mmol) and sodium hydroxide (0.053 mL, 0.053 mmol) in dioxane(1 mL) was heated up at 80° C. for 3 hours. The reaction mixture wasfiltered and the clear solution was purified by HPLC to provide thedesired product as white solid (1.6 mg, 39%). LCMS: m/e 742.65 (M−H)⁻,2.68 min (method 10). ¹H NMR (500 MHz, Acetic) δ 8.03 (d, J=8.2 Hz, 2H),7.30 (d, J=8.2 Hz, 2H), 5.37 (d, J=4.6 Hz, 1H), 4.86 (s, 1H), 4.75 (s,1H), 3.73 (br. s., 4H), 3.66-3.45 (m, 4H), 3.21 (br. s., 4H), 2.98-2.75(m, 1H), 2.31-1.00 (m, 22H), 1.77 (s, 3H), 1.50 (s, 9H), 1.23 (s, 3H),1.13 (s, 3H), 1.09 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).

Example B14 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 4-(methylsulfonyl)piperidine as the alkylating reagent inStep 3. The product was isolated as a white solid (200 mg, 84%). LCMS:m/e 719.58 (M+H)⁺, 2.31 min (method 11). ¹H NMR (500 MHz, Acetic) δ 8.04(d, J=8.5 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.37 (d, J=4.6 Hz, 1H), 4.87(s, 1H), 4.75 (s, 1H), 3.76-3.70 (m, 2H), 3.68-3.54 (m, 4H), 3.48-3.29(m, 1H), 3.18-3.03 (m, 2H), 3.02 (s, 3H), 2.84 (td, J=11.8, 4.7 Hz, 1H),2.46-1.03 (m, 26H), 1.77 (s, 3H), 1.22 (s, 3H), 1.14 (s, 3H), 1.10 (s,3H), 1.02 (s, 3H), 1.00 (s, 3H).

Example B15 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 1-(methylsulfonyl)piperazine as the alkylating reagent inStep 3. The product was isolated as a white solid (220 mg, 89%). LCMS:m/e 720.58 (M+H)⁺, 2.25 min (method 11). ¹H NMR (500 MHz, Acetic) δ 8.04(d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.37 (d, J=4.6 Hz, 1H), 4.86(s, 1H), 4.74 (s, 1H), 3.74-3.38 (m, 7H), 3.37-3.25 (m, 1H), 3.17 (br.s., 4H), 2.94 (s, 3H), 2.91-2.80 (m, 1H), 2.35-1.01 (m, 22H), 1.77 (s,3H), 1.26 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H), 1.00 (s,3H).

Example B16 Preparation of4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperazin-1-yl)ethyl)amino)icosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described inExample B2 for the synthesis of4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 1-(2-chloroethyl)-4-(methylsulfonyl)piperazine (prepared asdescribed below) as the alkylating reagent in Step 3. The product wasisolated as a white solid (11 mg, 56%). LCMS: m/e 724.6 (M+H)⁺, 2.44 min(method 10). ¹H NMR (500 MHz, Acetic) δ 8.02 (d, J=8.2 Hz, 2H), 7.36 (d,J=8.2 Hz, 2H), 3.63-3.29 (m, 7H), 3.25-3.14 (m, 1H), 3.13-2.99 (m, 4H),2.93 (s, 3H), 2.50 (dd, J=13.0, 2.6 Hz, 1H), 2.32-0.98 (m, 26H), 1.25(s, 3H), 1.12 (s, 3H), 1.08 (s, 3H), 0.93 (d, J=6.7 Hz, 3H), 0.86 (d,J=6.7 Hz, 3H), 0.83 (s, 3H), 0.79 (s, 3H).

Preparation of 1-(2-chloroethyl)-4-(methylsulfonyl)piperazine

A mixture of 1-(methylsulfonyl)piperazine (250 mg, 1.522 mmol),potassium carbonate (1262 mg, 9.13 mmol) and 1-bromo-2-chloroethane(1092 mg, 7.61 mmol) in acetonitrile (5 mL) was stirred for 6 hours atroom temperature. LCMS indicated the formation of desired product. Thereaction mixture was filtered to remove the white precipitate, thenquenched with distilled water (10 mL), extracted with ethyl acetate (3×8mL), the extracts were combined, dried over sodium sulfate, filtered andconcentrated under reduced pressure to provide the clean desired productas white solid (100 mg, 29%). LCMS: m/e 227.15 (M+H)⁺, 1.21 min (method10).

Example B17 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1,1-dioxidotetrahydrothiophen-3-yl)amino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 6-(2-chloroethyl)-2-oxa-6-azaspiro[3.3]heptane (prepared asdescribed below) as the alkylating reagent in Step 3. The product wasisolated as a white solid (1.1 mg, 18%). LCMS: m/e 655.53 (M+H)⁺, 2.29min (method 11). ¹H NMR (500 MHz, Acetic) δ 8.04 (d, J=8.2 Hz, 2H), 7.30(d, J=8.5 Hz, 2H), 5.37 (d, J=4.9 Hz, 1H), 4.93 (s., 4H), 4.86 (s, 1H),4.75 (br. s., 1H), 4.71-4.32 (m, 4H), 4.05-3.86 (m, 2H), 3.70-3.40 (m,2H), 3.00-2.66 (m, 1H), 2.25-1.05 (m, 22H), 1.76 (s, 3H), 1.18 (s, 3H),1.13 (s, 3H), 1.08 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).

Preparation of 6-(2-chloroethyl)-2-oxa-6-azaspiro[3.3]heptane

The title compound was prepared following the method described above forthe synthesis of 1-(2-chloroethyl)-4-(methylsulfonyl)piperazine using2-oxa-6-azaspiro[3.3]heptane as the starting reagent. The product wasisolated as colorless oil (10 mg, 12%). LCMS: m/e 162.15 (M+H)⁺, 0.87min (method 10).

Example B18 Preparation of4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)icosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described in abovefor the synthesis of4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 1-(2-chloroethyl)-4-(methylsulfonyl)piperidine (prepared asdescribed below) as the alkylating reagent in Step 3. The product wasisolated as a white solid (24 mg, 36%). LCMS: m/e 723.56 (M+H)⁺, 2.28min (method 11). ¹H NMR (500 MHz, Acetic) δ 8.02 (d, J=8.2 Hz, 2H), 7.36(d, J=8.2 Hz, 2H), 3.77-3.63 (m, 2H), 3.62-3.54 (m, 3H), 3.50 (d, J=5.5Hz, 1H), 3.35 (td, J=11.4, 3.7 Hz, 1H), 3.08-2.89 (m, 2H), 3.02 (s, 3H),2.50 (d, J=13.1 Hz, 1H), 2.42-2.29 (m, 2H), 2.28-1.03 (m, 28H), 1.21 (s,3H), 1.12 (s, 3H), 1.08 (s, 3H), 1.01 (d, J=11.3 Hz, 1H), 0.93 (d, J=6.7Hz, 4H), 0.86 (d, J=6.7 Hz, 4H), 0.83 (s, 3H), 0.79 (s, 3H).

Preparation of 1-(2-chloroethyl)-4-(methylsulfonyl)piperidine

Step 1. Preparation of 4-(methylsulfonyl)piperidine

A mixture of tert-butyl 4-(methylsulfonyl)piperidine-1-carboxylate (1.5g, 5.70 mmol) and hydrogen chloride (7.12 mL, 28.5 mmol) in THF (20 mL)was stirred at 20° C. for 15 hours. TLC indicated the formation ofdesired product, the reaction mixture was filtered and the pale yellowsolid was collected to provide desired product (1 g, 88%). LCMS: m/e163.96 (M+H)⁺, 0.25 min (method 10).

Step 2. Preparation of 2-(4-(methylsulfonyl)piperidin-1-yl)ethanol

A mixture of 4-(methylsulfonyl)piperidine hydrochloride (900 mg, 4.51mmol), 2-bromoethanol (1126 mg, 9.01 mmol) and potassium carbonate (1869mg, 13.52 mmol) in acetonitrile (4 mL) was heated up at 60° C. for 13hours. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to provide the crude, the crude waspurified by 0-35% ethyl acetate/methanol to provide the desired productas colorless oil (620 mg, 66%). LCMS: m/e 208.1 (M+H)⁺, 0.27 min (method6).

Step 3. Preparation of 1-(2-chloroethyl)-4-(methylsulfonyl)piperidine

A mixture of 2-(4-(methylsulfonyl)piperidin-1-yl)ethanol (620 mg, 2.99mmol) and thionyl chloride (1.092 mL, 14.95 mmol) in dichloroethane (5mL) was heated up at 74° C. for 4 hours. The reaction mixture wasconcentrated under reduced pressure to provide the crude, to the crudewas added THF (10 mL), the grey precipitate was observed and collected.The solid was dried under vacuum for 20 hour to provide the desiredproduct as grey solid (400 mg, 59%). LCMS: m/e 226.1 (M+H)⁺, 1.00 min(method 6).

Example B19 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(ethylsulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described in abovefor the synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 1-(ethylsulfonyl)piperazine as the alkylating reagent in Step3. The product was isolated as a white solid (11 mg, 53%). LCMS: m/e734.56 (M+H)⁺, 2.28 min (method 11). ¹H NMR (400 MHz, Acetic) δ 7.99 (d,J=8.5 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 5.34 (d, J=4.5 Hz, 1H), 4.81 (s,1H), 4.70 (s, 1H), 3.63-3.28 (m, 7H), 3.26-3.16 (m, 1H), 3.14-2.98 (m,6H), 2.95-2.75 (m, 1H), 2.33-1.06 (m, 22H), 1.73 (s, 3H), 1.32 (t, J=7.4Hz, 3H), 1.23 (s, 3H), 1.10 (s, 3H), 1.06 (s, 3H), 0.98 (s, 3H), 0.97(s, 3H).

Example B20 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatehydrochloride

A mixture of tert-butyl4-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)amino)ethyl)piperazine-1-carboxylate(150 mg, 0.198 mmol) and HCl (0.248 mL, 0.992 mmol) in THF (4 mL) wasstirred at 20° C. for 18 hours. The reaction mixture was concentratedunder reduced pressure to provide the desired product as brown solid(120 mg, 87%). LCMS: m/e 656.7 (M+H)⁺, 1.62 min (method 11).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(7.5 mg, 0.011 mmol) and sodium hydroxide (0.057 mL, 0.057 mmol) indioxane (1 mL) was heated up at 80° C. for 3 hours. The reaction mixturewas filtered and the clear solution was purified by HPLC to provide thedesired product as white solid (2.3 mg, 31%). LCMS: m/e 642.62 (M+H)⁺,2.29 min (method 11). ¹H NMR (400 MHz, Acetic) δ 8.00 (d, J=8.5 Hz, 2H),7.26 (d, J=8.5 Hz, 2H), 5.34 (d, J=4.8 Hz, 1H), 4.80 (s, 1H), 4.70 (s,1H), 3.59-3.28 (m, 6H), 3.25-3.11 (m, 1H), 3.09-2.73 (m, 6H), 2.31-1.15(m, 22H), 1.73 (s, 3H), 1.26 (s, 3H), 1.11 (s, 3H), 1.08 (s, 3H), 0.99(s, 3H), 0.97 (s, 3H).

Example B21 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylsulfonamido)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylsulfonamido)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-aminoethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(15 mg, 0.026 mmol) and Hunig's Base (0.013 mL, 0.077 mmol) indichloromethane (1 mL) was added methanesulfonyl chloride (3.81 mg,0.033 mmol) in dichloromethane (1 mL). The reaction mixture was stirredat 20° C. for 2 hours. The reaction mixture was diluted with distilledwater (3 mL), extracted with dichloromethane (3×3 mL), the extracts werecombined, dried over sodium sulfate, filtered and concentrated underreduced pressure to provide the desired product as a yellow solid (15mg, 88%). LCMS: m/e 665.55 (M+H)⁺, 2.44 min (method 11).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylsulfonamido)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylsulfonamido)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(15 mg, 0.023 mmol) and sodium hydroxide (0.113 mL, 0.113 mmol) indioxane (1 mL) was heated up at 80° C. for 3 hours. The reaction mixturewas filtered and the clear solution was purified by HPLC to provide thetitle compound as a white solid (7 mg, 45%). LCMS: m/e 651.52 (M+H)⁺,2.28 min (method 11). ¹H NMR (400 MHz, Acetic) δ 7.99 (d, J=8.3 Hz, 2H),7.26 (d, J=8.3 Hz, 2H), 5.33 (d, J=4.5 Hz, 1H), 4.81 (s, 1H), 4.71 (s,1H), 3.53 (br. s., 2H), 3.36-3.26 (m, 2H), 3.07 (s, 3H), 2.96-2.75 (m,1H), 2.30-2.11 (m, 3H), 1.84-1.06 (m, 19H), 1.74 (s, 3H), 1.22 (s, 3H),1.10 (s, 3H), 1.06 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H).

Example B22 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(cyclopropylsulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(cyclopropylsulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

To a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(26 mg, 0.040 mmol) and Hunig's Base (0.035 mL, 0.198 mmol) indichloromethane (1 mL) was added a solution of cyclopropanesulfonylchloride (11.14 mg, 0.079 mmol) in dichloromethane (1 mL) at roomtemperature. The reaction mixture was stirred for 2 hours at 20° C. orLCMS indicated the formation of desired product and consumption ofstarting material. The reaction mixture was diluted with distilled water(4 mL), extracted with dichloromethane (3×4 mL), the extracts werecombined, dried over sodium sulfate, filtered and concentrated underreduced pressure to provide the desired product as a yellow solid (30mg, 100%). LCMS: m/e 760.61 (M+H)⁺, 2.40 min (method 11).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(cyclopropylsulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(cyclopropylsulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(30 mg, 0.039 mmol) and sodium hydroxide (0.395 mL, 0.395 mmol) indioxane (0.5 mL) was heated up at 80° C. for 3 hours. The reactionmixture was filtered and the clear solution was purified by HPLC toprovide the title compound as a white solid (13 mg, 42%). LCMS: m/e746.58 (M+H)⁺, 2.27 min (method 11). ¹H NMR (400 MHz, Acetic) δ 7.99 (d,J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 5.34 (d, J=4.8 Hz, 1H), 4.81 (s,1H), 4.70 (s, 1H), 3.63-3.44 (m, 5H), 3.43-3.26 (m, 2H), 3.24-3.13 (m,1H), 3.05 (d, J=4.3 Hz, 4H), 2.86 (br. s., 1H), 2.58-2.40 (m, 1H),2.27-1.02 (m, 22H), 1.73 (s, 3H) 1.24 (s, 3H), 1.13 (d, J=4.5 Hz, 2H),1.10 (s, 3H), 1.06 (s, 3H), 1.02 (d, J=4.5 Hz, 2H), 0.97 (s, 3H), 0.96(s, 3H).

Example B23 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((2-(4-(propylsulfonyl)piperazin-1-yl)ethyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described in abovefor the synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(cyclopropylsulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using propane-1-sulfonyl chloride as the reagent in Step 1. Theproduct was isolated as a white solid (8 mg, 48%). LCMS: m/e 748.6(M+H)⁺, 2.30 min (method 11). ¹H NMR (400 MHz, Acetic) δ 7.99 (d, J=8.3Hz, 2H), 7.26 (d, J=8.5 Hz, 2H), 5.34 (d, J=4.5 Hz, 1H), 4.81 (s, 1H),4.70 (s, 1H), 3.59-3.26 (m, 7H), 3.23-3.11 (m, 1H), 3.09-2.95 (m, 6H),2.93-2.80 (m, 1H), 2.27-1.02 (m, 24H), 1.73 (s, 3H), 1.24 (s, 3H), 1.10(s, 3H), 1.07 (s, 3H), 1.05 (t, J=8.3 Hz, 3H), 0.98 (s, 3H), 0.97 (s,3H).

Example B24 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-acetylpiperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(cyclopropylsulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using acetyl chloride as the reagent in Step 1. The product wasisolated as a white solid (5.4 mg, 35%). LCMS: m/e 684.67 (M+H)⁺, 2.27min (method 11). ¹H NMR (400 MHz, Acetic) δ 7.99 (d, J=8.3 Hz, 2H), 7.26(d, J=8.5 Hz, 2H), 5.33 (d, J=4.8 Hz, 1H), 4.82 (s, 1H), 4.72 (s, 1H),4.09-3.89 (m, 1H), 3.85 (br. s., 3H), 3.68 (br. s., 4H), 3.53-3.14 (m,4H), 2.92-2.66 (m, 1H), 2.28-1.01 (m, 22H), 2.17 (s, 3H), 1.73 (s, 3H),1.18 (s, 3H), 1.10 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H).

Example B25 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(2-(dimethylamino)-2-oxoacetyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

Step 1. Preparation of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(2-(dimethylamino)-2-oxoacetyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(50 mg, 0.076 mmol),2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumtetrafluoroborate (29.4 mg, 0.091 mmol),N-ethyl-N-isopropylpropan-2-amine (11.82 mg, 0.091 mmol) and2-(dimethylamino)-2-oxoacetic acid (26.8 mg, 0.229 mmol) indichloromethane (2 mL) was stirred at 20° C. for 2 hours. The reactionmixture was diluted with distilled water (5 mL), extracted with ethylacetate (3×4 mL), the extracts were combined, dried over sodium sulfate,filtered and concentrated under reduced pressure to provide the desiredproduct as a yellow oil (40 mg, 70%). LCMS: m/e 755.68 (M+H)⁺, 2.42 min(method 11).

Step 2. Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(2-(dimethylamino)-2-oxoacetyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

A mixture of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(2-(dimethylamino)-2-oxoacetyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(40 mg, 0.053 mmol) and sodium hydroxide (0.530 mL, 0.530 mmol) indioxane (1 mL) was heated up at 82° C. for 3 hours. The reaction mixturewas cooled to room temperature, filtered and the clear solution waspurified by HPLC to provide the title compound as a white solid (17 mg,41%). LCMS: m/e 741.65 (M+H)⁺, 2.29 min (method 11). ¹H NMR (400 MHz,Acetic) δ 7.99 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 5.33 (d, J=4.5Hz, 1H), 4.82 (s, 1H), 4.71 (s, 1H), 4.14-3.78 (m, 2H), 3.75-3.36 (m,6H), 3.22 (br. s., 4H), 3.03 (s, 3H), 3.00 (s, 3H), 2.92-2.75 (m, 1H),2.29-1.05 (m, 22H), 1.73 (s, 3H), 1.20 (s, 3H), 1.10 (s, 3H), 1.05 (s,3H), 0.98 (s, 3H), 0.96 (s, 3H).

Example B26 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(isopropylsulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(cyclopropylsulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using propane-2-sulfonyl chloride as the reagent in Step 1. Theproduct was isolated as a colorless oil (6 mg, 36%). LCMS: m/e 748.63(M+H)⁺, 2.31 min (method 11). ¹H NMR (400 MHz, Acetic) δ 7.99 (d, J=8.0Hz, 2H), 7.26 (d, J=8.0 Hz, 2H), 5.33 (d, J=5.3 Hz, 1H), 4.82 (s, 1H),4.71 (s, 1H), 3.80-3.55 (m, 8H), 3.49-3.25 (m, 5H), 2.92-2.68 (m, 1H),2.32-1.04 (m, 22H), 1.73 (s, 3H), 1.32 (s, 3H), 1.30 (s, 3H), 1.17 (s,3H), 1.10 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H).

Example B27 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(tert-butyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 1-(tert-butyl)piperazine as the alkylating reagent in Step 3.The product was isolated as a white solid (9 mg, 40%). LCMS: m/e 698.67(M+H)⁺, 2.27 min (method 11). ¹H NMR (500 MHz, Acetic) δ 8.04 (d, J=8.0Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 5.38 (d, J=5.2 Hz, 1H), 4.84 (s, 1H),4.74 (s, 1H), 3.77 (br. s., 2H), 3.51-2.82 (m, 11H), 2.41-1.16 (m, 22H),1.77 (s, 3H), 1.49 (s, 9H), 1.30 (s, 3H), 1.15 (s, 3H), 1.10 (s, 3H),1.02 (s, 3H), 1.01 (s, 3H).

Example B28 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-methylpiperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described in abovefor the synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 1-methylpiperazine as the alkylating reagent in Step 3. Theproduct was isolated as a white solid (3 mg, 19%). LCMS: m/e 656.62(M+H)⁺, 2.19 min (method 11). ¹H NMR (500 MHz, Acetic) δ 8.04 (d, J=8.0Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 5.38 (d, J=5.7 Hz, 1H), 4.84 (s, 1H),4.74 (s, 1H), 3.73 (br. s., 1H), 3.62-2.85 (m, 12H), 2.94 (s, 3H),2.34-1.15 (m, 22H), 1.77 (s, 3H), 1.29 (s, 3H), 1.15 (s, 3H), 1.11 (s,3H), 1.03 (s, 3H), 1.01 (s, 3H).

Example B29 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(2-oxo-2-(piperidin-1-yl)acetyl)piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(2-(dimethylamino)-2-oxoacetyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 2-oxo-2-(piperidin-1-yl)acetic acid as the acid in Step 1.The product was isolated as a white solid (1.1 mg, 18%). LCMS: m/e 781.7(M+H)⁺, 1.72 min (method 11). ¹H NMR (500 MHz, CHLOROFORM-d) δ 7.99 (d,J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 5.31 (d, J=4.6 Hz, 1H), 4.77 (s,1H), 4.65 (s, 1H), 3.84 (dd, J=7.6, 2.7 Hz, 1H), 3.68-3.56 (m, 3H), 3.49(t, J=4.9 Hz, 2H), 3.43-3.30 (m, 2H), 2.93-2.63 (m, 9H), 2.60-1.05 (m,28H), 1.72 (s, 3H), 1.17 (s, 3H), 1.04 (s, 3H), 1.00 (s, 3H), 0.97 (s,3H), 0.97 (s, 3H).

Example B30 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(1-methylethylsulfonamido)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylsulfonamido)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using propane-2-sulfonyl chloride as the reagent in Step 1. Theproduct was isolated as a colorless oil (3.5 mg, 34%). LCMS: m/e 679.55(M+H)⁺, 2.36 min (method 11). ¹H NMR (400 MHz, CHLOROFORM-d) δ 9.56 (br.s., 1H), 7.98 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.3 Hz, 2H), 6.91 (t, J=6.3Hz, 1H), 5.94 (br. s., 1H), 5.18 (d, J=4.5 Hz, 1H), 4.87 (s, 1H), 4.71(s, 1H), 3.88-3.69 (m, 1H), 3.63-3.49 (m, 1H), 3.37-3.16 (m, 3H),2.90-2.68 (m, 1H), 2.26-1.07 (m, 22H), 1.70 (s, 3H), 1.44 (dd, J=8.8,6.8 Hz, 6H), 1.20 (s, 3H), 1.02 (s, 3H), 0.96 (s, 3H), 0.96 (s, 3H),0.92 (s, 3H).

Example B31 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(cyclopropanesulfonamido)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylsulfonamido)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using cyclopropanesulfonyl chloride as the reagent in Step 1. Theproduct was isolated as a colorless oil (3.5 mg, 34%). LCMS: m/e 677.52(M+H)⁺, 2.32 min (method 11). ¹H NMR (400 MHz, CHLOROFORM-d) δ 9.55 (br.s., 1H), 7.98 (d, J=8.3 Hz, 2H), 7.23 (d, J=8.3 Hz, 2H), 6.76 (br. s.,1H), 5.99 (br. s., 1H), 5.21 (d, J=5.0 Hz, 1H), 4.85 (s, 1H), 4.71 (s,1H), 3.92-3.71 (m, 1H), 3.69-3.55 (m, 1H), 3.23 (br. s., 2H), 2.91-2.70(m, 1H), 2.63-2.44 (m, 1H), 2.25-1.02 (m, 26H), 1.70 (s, 3H), 1.18 (s,3H), 1.02 (s, 3H), 0.97 (s, 3H), 0.92 (s, 3H), 0.92 (s, 3H).

Example B32 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-1,2-thiazinan-2-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1,1-dioxidotetrahydrothiophen-3-yl)amino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using 1-(2-chloroethyl)-4-(methylsulfonyl)piperazine (prepared asdescribed below) as the alkylating reagent in Step 3. The product wasisolated as a white solid (5.2 mg, 36%). LCMS: m/e 691.55 (M+H)⁺, 2.35min (method 11). ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.99 (d, J=8.3 Hz,2H), 7.23 (d, J=8.5 Hz, 2H), 5.27 (d, J=4.5 Hz, 1H), 4.82 (s, 1H), 4.70(s, 1H), 3.87-3.74 (m, 1H), 3.72-3.48 (m, 3H), 3.39 (br. s., 2H),3.18-3.08 (m, 2H), 2.96-2.78 (m, 1H), 2.34-1.10 (m, 26H), 1.71 (s, 3H),1.23 (s, 3H), 1.05 (s, 3H), 0.99 (s, 3H), 0.96 (s, 3H), 0.96 (s, 3H).

Preparation of 1-(2-chloroethyl)-4-(methylsulfonyl)piperazine

The title compound was prepared following the method described inpreviously for the synthesis of1-(2-chloroethyl)-4-(methylsulfonyl)piperazine using 1,2-thiazinane1,1-dioxide as the starting reagent and sodium hydride as the base. Theproduct was isolated as colorless oil (120 mg, 41%). LCMS: m/e 198.08(M+H)⁺, 1.24 min (method 11).

Example B33 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(ethylsulfonamido)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylsulfonamido)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using ethanesulfonyl chloride as the reagent in Step 1. The productwas isolated as a white solid (8.7 mg, 56%). LCMS: m/e 665.46 (M+H)⁺,2.29 min (method 11). ¹H NMR (500 MHz, CHLOROFORM-d) δ 9.27 (br. s.,1H), 8.00 (d, J=7.1 Hz, 2H), 7.25 (d, J=7.1 Hz, 2H), 6.84 (br. s., 1H),6.07 (br. s., 1H), 5.24 (d, J=6.3 Hz, 1H), 4.85 (s, 1H), 4.73 (s, 1H),3.84-3.68 (m, 1H), 3.54 (d, J=14.8 Hz, 1H), 3.37-3.21 (m, 2H), 3.17 (q,J=7.4 Hz, 2H), 2.83-2.76 (m, 1H), 2.36-0.95 (m, 22H), 1.72 (s, 3H), 1.46(t, J=7.4 Hz, 3H), 1.20 (s, 3H), 1.05 (s, 3H), 0.97 (s, 3H), 0.95 (s,3H), 0.95 (s, 3H).

Example B34 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((2-(propylsulfonamido)ethyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared following the method described above forthe synthesis of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylsulfonamido)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid using propane-1-sulfonyl chloride as the reagent in Step 1. Theproduct was isolated as a white solid (9 mg, 49%). LCMS: m/e 679.48(M+H)⁺, 2.34 min (method 11). ¹H NMR (500 MHz, CHLOROFORM-d) δ 9.36 (br.s., 1H), 8.00 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 6.81 (br. s.,1H), 6.04 (br. s., 1H), 5.31-5.19 (m, 1H), 4.86 (s, 1H), 4.73 (s, 1H),3.85-3.67 (m, 1H), 3.54 (d, J=14.7 Hz, 1H), 3.38-3.18 (m, 2H), 3.15-3.07(m, 2H), 2.80 (td, J=11.2, 5.9 Hz, 1H), 2.26-0.95 (m, 24H), 1.71 (s,3H), 1.20 (s, 3H), 1.12 (t, J=7.4 Hz, 3H), 1.05 (s, 3H), 0.97 (s, 3H),0.96 (s, 3H), 0.94 (s, 3H).

General Procedure for the Preparation of Examples B35-B-52.

To the corresponding substituted sulfonyl chloride reagent(sulfonylating agent) (0.075 mmol) was added a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(29 mg, 0.044 mmol) and DIPEA (0.039 mL, 0.221 mmols) in DCE (1 mL) atroom temperature. The reaction mixture was stirred overnight at roomtemperature. The solvent was evaporated to provide the dry residue. Tothe residue in dioxane (0.8 mL) was added a solution of lithiumhydroxide monohydrate (14.7 mg, 0.35 mmol) in water (0.2 mL). Thereaction mixture was agitated at 350 rpm on an Innova platform shaker at70° C. overnight. The solvent was removed and DMF (1.5 mL) was added.The mixture was filtered and the clear solution was purified by HPLC toprovide the desired products with yield ranged from 6-50% over twosteps.

Example B35 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(isobutylsulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared to provide 11.9 mg from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above usingisobutanesulfonyl chloride as the sulfonylating agent. LCMS: m/e 762.8(M+H)⁺, 3.65 min (method 14). ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (d, J=8.2Hz, 2H), 7.22 (d, J=8.2 Hz, 2H), 5.25 (d, J=4.9 Hz, 1H), 4.70 (s, 1H),4.57 (s, 1H), 3.17 (br. s., 4H), 3.00-2.82 (m, 2H), 2.70-2.53 (m, 5H),2.48-2.30 (m, 4H), 2.24-2.03 (m, 2H), 2.00-1.83 (m, 2H), 1.80-1.01 (m,19H), 1.67 (s, 3H), 1.11 (s, 3H), 1.06 (s, 3H), 1.05 (s, 3H), 0.98 (s,3H), 0.96 (s, 3H), 0.90 (s, 3H), 0.88 (s, 3H).

Example B36 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((2-(4-(pyridin-3-ylsulfonyl)piperazin-1-yl)ethyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared to provide 12.7 mg from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above usingpyridine-3-sulfonyl chloride as the sulfonylating agent. LCMS: m/e 783.8(M+H)⁺, 3.42 min (method 14). ¹H NMR (500 MHz, DMSO-d₆) δ 8.95 (d, J=2.1Hz, 1H), 8.89 (dd, J=4.7, 1.4 Hz, 1H), 8.32-8.16 (m, 1H), 7.88 (d, J=8.2Hz, 2H), 7.73 (dd, J=7.9, 4.9 Hz, 1H), 7.25 (d, J=7.9 Hz, 2H), 5.25 (d,J=4.9 Hz, 1H), 4.64 (d, J=1.8 Hz, 1H), 4.53 (s, 1H), 3.11-2.92 (m, 4H),2.65-2.46 (m, 5H), 2.45-2.20 (m, 4H), 2.05 (dd, J=17.4, 6.4 Hz, 1H),1.91-1.76 (m, 2H), 1.73-0.99 (m, 19H), 1.63 (s, 3H), 1.03 (s, 3H), 0.94(s, 3H), 0.91 (s, 3H), 0.87 (s, 3H), 0.61 (s, 3H).

Example B37 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(N,N-diethylsulfamoyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared to provide 10.6 mg from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above usingdimethylsulfamoyl chloride as the sulfonylating agent. LCMS: m/e 777.8(M+H)⁺, 3.82 min (method 14). ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (d, J=7.9Hz, 2H), 7.22 (d, J=8.2 Hz, 2H), 5.25 (d, J=4.6 Hz, 1H), 4.70 (d, J=2.1Hz, 1H), 4.56 (s, 1H), 3.22 (q, J=7.1 Hz, 4H), 3.08 (br. s., 4H),2.69-2.57 (m, 1H), 2.56-2.47 (m, 4H), 2.44-2.31 (m, 4H), 2.08 (dd,J=17.5, 6.3 Hz, 1H), 1.95-1.00 (m, 21H), 1.67 (s, 3H), 1.12 (t, J=7.0Hz, 6H), 1.09 (s, 3H), 0.97 (s, 3H), 0.96 (s, 3H), 0.91 (s, 3H), 0.90(s, 3H).

Example B38 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-((3-chloropropyl)sulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared to provide 10.9 mg from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above using3-chloropropanesulfonyl chloride as the sulfonylating agent. LCMS: m/e782.7 (M+H)⁺, 3.59 min (method 14). ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (d,J=7.9 Hz, 2H), 7.22 (d, J=8.2 Hz, 2H), 5.25 (d, J=4.9 Hz, 1H), 4.70 (d,J=2.1 Hz, 1H), 4.57 (s, 1H), 3.76 (t, J=6.4 Hz, 2H), 3.26-3.13 (m, 6H),2.63 (td, J=10.5, 4.9 Hz, 1H), 2.56 (d, J=7.6 Hz, 4H), 2.48-2.33 (m,4H), 2.21-2.04 (m, 3H), 1.98-1.83 (m, 2H), 1.83-1.02 (m, 19H), 1.67 (s,3H), 1.10 (s, 3H), 0.98 (s, 3H), 0.97 (s, 3H), 0.90 (s, 3H), 0.90 (s,3H).

Example B39 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(butylsulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared to provide 13.6 mg from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above usingbutane-1-sulfonyl chloride as the sulfonylating agent. LCMS: m/e 762.8(M+H)⁺, 3.66 min (method 14). ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (d, J=8.2Hz, 2H), 7.22 (d, J=8.2 Hz, 2H), 5.25 (d, J=4.6 Hz, 1H), 4.70 (d, J=2.1Hz, 1H), 4.56 (s, 1H), 3.19 (br. s., 4H), 3.12-2.96 (m, 2H), 2.63 (td,J=10.8, 5.3 Hz, 1H), 2.55 (br. s., 4H), 2.47-2.30 (m, 4H), 2.08 (dd,J=17.2, 6.3 Hz, 1H), 1.98-1.83 (m, 2H), 1.82-1.02 (m, 23H), 1.67 (s,3H), 1.10 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H), 0.91 (t, J=4.7 Hz, 3H),0.90 (s, 3H), 0.89 (s, 3H).

Example B40 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-((4-ethylphenyl)sulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared to provide 3.7 mg from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above using4-ethyl-benzene-1-sulfonyl chloride as the sulfonylating agent. LCMS:m/e 810.9 (M+H)⁺, 4.12 min (method 14). ¹H NMR (500 MHz, DMSO-d₆) δ 7.89(d, J=8.2 Hz, 2H), 7.68 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.2 Hz, 2H), 7.24(d, J=8.2 Hz, 2H), 5.26 (d, J=4.9 Hz, 1H), 4.63 (br. s., 1H), 4.55 (br.s., 1H), 3.03-2.90 (m, 4H), 2.71 (q, J=7.7 Hz, 2H), 2.52 (d, J=1.5 Hz,5H), 2.49-2.34 (m, 4H), 2.06 (dd, J=17.7, 6.4 Hz, 1H), 1.80 (d, J=9.8Hz, 2H), 1.75-1.01 (m, 19H), 1.63 (s, 3H), 1.21 (t, J=7.5 Hz, 3H), 0.96(s, 3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.92 (s, 3H), 0.85 (s, 3H).

Example B41 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(benzylsulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared to provide 16.4 mg from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above usingphenyl-methanesulfonyl chloride as the sulfonylating agent. LCMS: m/e796.8 (M+H)⁺, 3.73 min (method 14). ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (d,J=8.2 Hz, 2H), 7.46-7.41 (m, 2H), 7.41-7.31 (m, 3H), 7.22 (d, J=8.2 Hz,2H), 5.25 (d, J=4.6 Hz, 1H), 4.72 (d, J=1.5 Hz, 1H), 4.58 (s, 1H),4.53-4.39 (m, 2H), 3.11 (br. s., 4H), 2.64-2.54 (m, 1H), 2.53-2.45 (m,2H), 2.46-2.29 (m, 6H), 2.09 (dd, J=17.2, 6.3 Hz, 1H), 1.96-1.80 (m,3H), 1.78-1.02 (m, 18H), 1.68 (s, 3H), 1.10 (s, 3H), 0.98 (s, 3H), 0.97(s, 3H), 0.89 (s, 3H), 0.87 (s, 3H).

Example B42 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(((methylsulfonyl)methyl)sulfonyl)piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared to provide 5.5 mg from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above usingmethanesulfonyl-methanesulfonyl chloride as the sulfonylating agent.LCMS: m/e 798.8 (M+H)⁺, 3.28 min (method 14). ¹H NMR (500 MHz, DMSO-d₆)δ 7.87 (d, J=7.9 Hz, 2H), 7.22 (d, J=7.9 Hz, 2H), 5.29 (s, 2H), 5.25 (d,J=4.6 Hz, 1H), 4.70 (s, 1H), 4.57 (s, 1H), 3.29 (br. s., 8H), 3.19 (s,3H), 2.64-2.55 (m, 1H), 2.48-2.34 (m, 4H), 2.08 (dd, J=17.2, 6.3 Hz,1H), 1.97-1.80 (m, 3H), 1.79-0.99 (m, 18H), 1.67 (s, 3H), 1.09 (s, 3H),0.97 (s, 3H), 0.97 (s, 3H), 0.90 (s, 3H), 0.90 (s, 3H).

Example B43 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared to provide 17 mg from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above using1-methyl-1H-imidazole-4-sulfonyl chloride as the sulfonylating agent.LCMS: m/e 786.8 (M+H)⁺, 3.08 min (method 14). ¹H NMR (500 MHz, DMSO-d₆)δ 7.92-7.84 (m, 3H), 7.77 (s, 1H), 7.23 (d, J=7.9 Hz, 2H), 5.26 (d,J=4.9 Hz, 1H), 4.66 (d, J=1.8 Hz, 1H), 4.55 (s, 1H), 3.73 (s, 3H), 3.04(br. s., 4H), 2.63-2.47 (m, 5H), 2.45-2.26 (m, 4H), 2.08 (dd, J=17.4,6.4 Hz, 1H), 1.91-1.77 (m, 2H), 1.77-1.00 (m, 19H), 1.65 (s, 3H), 0.96(s, 3H), 0.94 (s, 3H), 0.94 (s, 3H), 0.93 (s, 3H), 0.89 (s, 3H).

Example B44 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(phenylsulfonyl)piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared to provide 3.9 mg from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above using benzenesulfonylchloride as the sulfonylating agent. LCMS: m/e 782.8 (M+H)⁺, 4.98 min(method 15). ¹H NMR (500 MHz, DMSO-d₆) δ 7.89 (d, J=8.2 Hz, 2H), 7.78(d, J=7.0 Hz, 2H), 7.75-7.62 (m, 3H), 7.26 (d, J=7.9 Hz, 2H), 5.25 (d,J=4.9 Hz, 1H), 4.64 (br. s., 1H), 4.54 (br. s., 1H), 2.92 (br. s., 4H),2.57 (br. s., 5H), 2.47-2.27 (m, 4H), 2.05 (dd, J=17.4, 6.4 Hz, 1H),1.93-1.77 (m, 2H), 1.76-0.98 (m, 19H), 1.63 (s, 3H), 1.03 (s, 3H), 0.95(s, 3H), 0.91 (s, 3H), 0.86 (s, 3H), 0.58 (s, 3H).

Example B45 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-((3-methoxyphenyl)sulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared to provide 3.2 mg from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above using3-methoxybenzenesulfonyl chloride as the sulfonylating agent. LCMS: m/e812.8 (M+H)⁺, 4.98 min (method 15). ¹H NMR (500 MHz, DMSO-d₆) δ 7.89 (d,J=8.2 Hz, 2H), 7.64-7.51 (m, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.28-7.13 (m,4H), 5.25 (d, J=4.6 Hz, 1H), 4.64 (s, 1H), 4.53 (s, 1H), 3.85 (s, 3H),3.03-2.87 (m, 4H), 2.64-2.51 (m, 5H), 2.46-2.22 (m, 4H), 2.05 (dd,J=17.2, 6.3 Hz, 1H), 1.93-1.76 (m, 2H), 1.75-0.98 (m, 19H), 1.63 (s,3H), 1.02 (s, 3H), 0.94 (s, 3H), 0.91 (s, 3H), 0.87 (s, 3H), 0.63 (s,3H).

Example B46 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared to provide 2.1 mg from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above using4-chlorobenzene-1-sulfonyl chloride as the sulfonylating agent. LCMS:m/e 816.8 (M+H)⁺, 3.94 min (method 14). ¹H NMR (500 MHz, DMSO-d₆) δ 7.89(d, J=8.2 Hz, 2H), 7.81 (d, J=8.5 Hz, 2H), 7.73 (d, J=8.9 Hz, 2H), 7.24(d, J=7.9 Hz, 2H), 5.25 (d, J=4.6 Hz, 1H), 4.66 (br. s., 1H), 4.57 (br.s., 1H), 2.96 (br. s., 4H), 2.71-2.55 (m, 4H), 2.51-2.30 (m, 5H), 2.06(dd, J=17.4, 6.4 Hz, 1H), 1.98-1.79 (m, 2H), 1.78-0.89 (m, 19H), 1.65(s, 3H), 1.00 (s, 3H), 0.93 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.80(s, 3H).

Example B47 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-((4-methoxyphenyl)sulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared to provide 9.5 mg from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above using4-methoxybenzene-1-sulfonyl chloride as the sulfonylating agent. LCMS:m/e 812.8 (M+H)⁺, 3.69 min (method 14). ¹H NMR (500 MHz, DMSO-d₆) δ 7.89(d, J=8.2 Hz, 2H), 7.70 (d, J=8.9 Hz, 2H), 7.24 (d, J=8.2 Hz, 2H), 7.16(d, J=8.9 Hz, 2H), 5.25 (d, J=4.6 Hz, 1H), 4.63 (d, J=2.1 Hz, 1H), 4.53(s, 1H), 3.83 (s, 3H), 2.91 (s, 4H), 2.61-2.46 (m, 5H), 2.41 (br. s.,2H), 2.36-2.22 (m, 2H), 2.05 (dd, J=17.5, 6.3 Hz, 1H), 1.90-1.75 (m,2H), 1.74-1.03 (m, 19H), 1.63 (s, 3H), 0.98 (s, 3H), 0.92 (s, 3H), 0.92(s, 3H), 0.88 (s, 3H), 0.75 (s, 3H).

Example B48 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((2-(4-tosylpiperazin-1-yl)ethyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared to provide 4.6 mg from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above using4-methylbenzene-1-sulfonyl chloride as the sulfonylating agent. LCMS:m/e 796.8 (M+H)⁺, 3.91 min (method 14). ¹H NMR (500 MHz, DMSO-d₆) δ 7.88(d, J=8.2 Hz, 2H), 7.65 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 7.24(d, J=7.9 Hz, 2H), 5.25 (d, J=4.6 Hz, 1H), 4.62 (d, J=2.1 Hz, 1H), 4.53(s, 1H), 2.91 (s, 4H), 2.59-2.45 (m, 5H), 2.41 (s, 5H), 2.36-2.25 (m,2H), 2.06 (dd, J=17.4, 6.4 Hz, 1H), 1.88-1.74 (m, 2H), 1.73-0.99 (m,19H), 1.63 (s, 3H), 0.97 (s, 3H), 0.92 (s, 3H), 0.92 (s, 3H), 0.91 (s,3H), 0.81 (s, 3H).

Example B49 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(naphthalen-1-ylsulfonyl)piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared to provide 3.0 mg from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above usingnaphthalene-1-sulfonyl chloride as the sulfonylating agent. LCMS: m/e832.8 (M+H)⁺, 4.00 min (method 14). ¹H NMR (500 MHz, DMSO-d₆) δ 8.75 (d,J=8.5 Hz, 1H), 8.29 (d, J=7.9 Hz, 1H), 8.17 (d, J=7.3 Hz, 1H), 8.10 (d,J=8.2 Hz, 1H), 7.90 (d, J=7.9 Hz, 2H), 7.81-7.62 (m, 3H), 7.28 (d, J=7.9Hz, 2H), 5.24 (d, J=5.5 Hz, 1H), 4.62 (br. s., 1H), 4.52 (br. s., 1H),3.08 (br. s., 4H), 2.52 (br. s., 5H), 2.45-2.22 (m, 4H), 2.02 (dd,J=17.7, 6.1 Hz, 1H), 1.91-1.74 (m, 2H), 1.73-1.02 (m, 19H), 1.61 (s,3H), 1.06 (s, 3H), 0.94 (s, 3H), 0.87 (s, 3H), 0.79 (s, 3H), 0.48 (s,3H).

Example B50 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared to provide 5.7 mg from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above using4-fluorobenzene-1-sulfonyl chloride as the sulfonylating agent. LCMS:m/e 800.8 (M+H)⁺, 4.95 min (method 15). ¹H NMR (500 MHz, DMSO-d₆) δ7.93-7.80 (m, 4H), 7.50 (t, J=8.7 Hz, 2H), 7.24 (d, J=7.9 Hz, 2H), 5.25(d, J=4.9 Hz, 1H), 4.64 (d, J=2.1 Hz, 1H), 4.53 (s, 1H), 3.05-2.84 (m,4H), 2.64-2.47 (m, 5H), 2.40 (br. s., 2H), 2.35-2.22 (m, 2H), 2.05 (dd,J=17.2, 6.3 Hz, 1H), 1.90-0.97 (m, 21H), 1.63 (s, 3H), 0.99 (s, 3H),0.93 (s, 3H), 0.91 (s, 3H), 0.87 (s, 3H), 0.67 (s, 3H).

Example B51 Preparation of4-((4-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-carboxyphenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)amino)ethyl)piperazin-1-yl)sulfonyl)benzoicacid

The title compound was prepared to provide 10.1 mg from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above using4-(chlorosulfonyl)benzoic acid as the sulfonylating agent. LCMS: m/e826.8 (M+H)⁺, 2.75 min (method 14). ¹H NMR (500 MHz, DMSO-d₆) δ 8.18 (d,J=8.2 Hz, 2H), 7.89 (dd, J=8.4, 3.8 Hz, 4H), 7.25 (d, J=8.2 Hz, 2H),5.23 (d, J=4.9 Hz, 1H), 4.63 (s, 1H), 4.54 (s, 1H), 3.10-2.93 (m, 4H),2.68-2.53 (m, 5H), 2.49-2.32 (m, 4H), 2.03 (dd, J=17.2, 6.0 Hz, 1H),1.90-1.76 (m, 2H), 1.75-0.99 (m, 19H), 1.63 (s, 3H), 0.95 (s, 3H), 0.91(s, 3H), 0.90 (s, 3H), 0.85 (s, 3H), 0.77 (s, 3H).

Example B52 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound was prepared to provide 13.2 mg from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above using2,3-dihydro-1,4-benzodioxine-6-sulfonyl chloride as the sulfonylatingagent. LCMS: m/e 840.8 (M+H)⁺, 3.66 min (method 14). ¹H NMR (500 MHz,DMSO-d₆) δ 7.88 (d, J=8.2 Hz, 2H), 7.31-7.18 (m, 4H), 7.08 (d, J=8.2 Hz,1H), 5.25 (d, J=4.6 Hz, 1H), 4.64 (d, J=2.1 Hz, 1H), 4.54 (s, 1H),4.42-4.21 (m, 4H), 2.91 (s, 4H), 2.62-2.51 (m, 5H), 2.41 (br. s., 2H),2.36-2.26 (m, 2H), 2.06 (dd, J=17.4, 6.4 Hz, 1H), 1.90-1.76 (m, 2H),1.75-0.88 (m, 19H), 1.64 (s, 3H), 0.98 (s, 3H), 0.93 (s, 3H), 0.92 (s,3H), 0.91 (s, 3H), 0.78 (s, 3H).

General Procedure for the Preparation of Examples B53-B64

A solution of the corresponding substituted carboxylic acid (acylatingagent) (0.039 mmol) and HATU (14.78 mg, 0.039 mmol) in DMF (0.5 mL) wasstirred for 10 minutes, then a solution of methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate(17 mg, 0.026 mmol) and DIPEA (0.018 mL, 0.104 mmol) in DMF (0.500 mL)was introduced. The reaction mixture was agitated at 350 rpm on anInnova platform shaker at room temperature overnight. The solvent wasevaporated to provide the dry residue. To the residue in dioxane (0.8mL) was added the lithium hydroxide monohydrate (8.70 mg, 0.207 mmol)dissolved in water (0.2 mL). The reaction mixture was stirred at 80° C.overnight. The solvent was removed and DMF (1.0 mL) was added. Themixture was filtered and the clear solution was purified by HPLC toprovide the desired products with yield ranged from 2-31% over twosteps.

Example B53 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(cyclohexanecarbonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound (4.9 mg) was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above usingcyclohexanecarboxylic acid as the acylating agent. LCMS: m/e 752.8(M+H)⁺, 3.90 min (method 14). ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (d, J=8.2Hz, 2H), 7.19 (d, J=8.2 Hz, 2H), 5.24 (d, J=4.9 Hz, 1H), 4.70 (s, 1H),4.56 (s, 1H), 3.49 (br. s., 4H), 2.70-2.53 (m, 4H), 2.48-2.31 (m, 5H),2.31-2.18 (m, 1H), 2.08 (dd, J=17.4, 6.1 Hz, 1H), 1.99-1.79 (m, 3H),1.78-1.00 (m, 28H), 1.67 (s, 3H), 1.08 (s., 3H), 0.97 (s, 3H), 0.96 (s,3H), 0.90 (s, 3H), 0.90 (s, 3H).

Example B54 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(cyclobutanecarbonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound (3.1 mg) was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above usingcyclobutanecarboxylic acid as the acylating agent. LCMS: m/e 724.8(M+H)⁺, 3.66 min (method 14). ¹H NMR (500 MHz, METHANOL-d₄) δ 7.89 (d,J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 5.30 (d, J=4.6 Hz, 1H), 4.79 (s,1H), 4.68 (s, 1H), 3.83-3.54 (m, 2H), 3.53-3.38 (m, 3H), 2.91 (d, J=2.1Hz, 1H), 2.85-2.71 (m, 2H), 2.62 (d, J=10.1 Hz, 3H), 2.55-2.39 (m, 2H),2.36-1.18 (m, 29H), 1.75 (s, 3H), 1.22 (s., 3H), 1.11 (s, 3H), 1.05 (s,3H), 0.97 (s, 3H), 0.96 (s, 3H).

Example B55 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(cyclopentanecarbonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound (3.1 mg) was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above usingcyclopentanecarboxylic acid as the acylating agent. LCMS: m/e 738.8(M+H)⁺, 3.84 min (method 14). ¹H NMR (500 MHz, METHANOL-d₄) δ 7.89 (d,J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 5.30 (d, J=4.6 Hz, 1H), 4.79 (s,1H), 4.69 (s, 1H), 3.78-3.52 (m, 4H), 3.13-3.01 (m, 2H), 2.97-2.89 (m,1H), 2.86-2.73 (m, 2H), 2.72-2.61 (m, 3H), 2.60-2.41 (m, 2H), 2.20-1.80(m, 8H), 1.75 (s, 3H), 1.74-1.18 (m, 22H), 1.23 (s., 3H), 1.11 (s, 3H),1.06 (s, 3H), 0.97 (s, 3H), 0.97 (s, 3H).

Example B56 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(2-cyclopentylacetyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound (3.1 mg) was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above usingcyclopentylacetic acid as the acylating agent. LCMS: m/e 752.9 (M+H)⁺,3.93 min (method 14). ¹H NMR (500 MHz, METHANOL-d₄) δ 7.89 (d, J=8.2 Hz,2H), 7.17 (d, J=8.2 Hz, 2H), 5.30 (d, J=4.6 Hz, 1H), 4.80 (s, 1H), 4.69(s, 1H), 3.70 (br. s., 1H), 3.66-3.53 (m, 3H), 3.12-3.01 (m, 1H),2.95-2.89 (m, 1H), 2.86-2.72 (m, 2H), 2.71-2.61 (m, 3H), 2.60-2.54 (m,1H), 2.51-2.47 (m, 1H), 2.45 (d, J=7.3 Hz, 2H), 2.27-1.90 (m, 6H),1.89-1.79 (m, 3H), 1.76 (s, 3H), 1.73-1.18 (m, 22H), 1.23 (s, 3H), 1.11(s, 3H), 1.06 (s, 3H), 0.97 (s, 3H), 0.97 (s, 3H).

Example B57 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(2-cyclohexylacetyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound (3.4 mg) was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above usingcyclopentylacetic acid as the acylating agent. LCMS: m/e 766.9 (M+H)⁺,4.09 min (method 14). ¹H NMR (500 MHz, METHANOL-d₄) δ 7.89 (d, J=8.2 Hz,2H), 7.17 (d, J=8.2 Hz, 2H), 5.30 (d, J=4.9 Hz, 1H), 4.79 (s, 1H), 4.69(s, 1H), 3.72 (dd, J=10.5, 6.0 Hz, 1H), 3.67-3.53 (m, 3H), 3.11-3.01 (m,1H), 2.92 (d, J=10.7 Hz, 1H), 2.87-2.72 (m, 2H), 2.71-2.60 (m, 3H),2.60-2.53 (m, 1H), 2.51-2.41 (m, 1H), 2.31 (d, J=6.4 Hz, 2H), 2.20-1.90(m, 5H), 1.84 (td, J=12.1, 3.4 Hz, 1H), 1.75 (s, 3H), 1.75-1.02 (m,27H), 1.23 (s, 3H), 1.11 (s, 3H), 1.06 (s, 3H), 0.97 (s, 3H), 0.97 (s,3H).

Example B58 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(2-phenylpropanoyl)piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound (4.1 mg) was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above using2-phenylpropionic acid as the acylating agent. LCMS: m/e 774.9 (M+H)⁺,3.87 min (method 14). ¹H NMR (500 MHz, METHANOL-d₄) δ 7.89 (d, J=7.0 Hz,2H), 7.41-7.31 (m, 2H), 7.29-7.22 (m, 3H), 7.18 (dd, J=8.2, 3.1 Hz, 2H),5.30 (d, J=4.9 Hz, 1H), 4.77 (s, 1H), 4.67 (s, 1H), 4.11 (quin, J=6.4Hz, 1H), 3.89-3.44 (m, 4H), 2.99-2.92 (m, 1H), 2.86-2.67 (m, 3H),2.67-2.57 (m, 1H), 2.51 (d, J=13.7 Hz, 2H), 2.46-2.27 (m, 2H), 2.21-2.09(m, 2H), 2.07-1.85 (m, 4H), 1.80-1.15 (m, 16H), 1.74 (s, 3H), 1.40 (d,J=6.7 Hz, 3H), 1.09 (d, J=8.5 Hz, 3H), 1.07 (d, J=13 Hz, 3H), 1.04 (s,3H), 1.01 (s, 3H), 0.98 (s, 3H).

Example B59 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(3-methylbutanoyl)piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound (3.3 mg) was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above using isovaleric acidas the acylating agent. LCMS: m/e 726.8 (M+H)⁺, 3.71 min (method 14). ¹HNMR (500 MHz, METHANOL-d₄) δ 7.89 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz,2H), 5.30 (d, J=4.9 Hz, 1H), 4.79 (s, 1H), 4.69 (s, 1H), 3.77-3.55 (m,4H), 3.09-3.02 (m, 1H), 2.91 (br. s., 1H), 2.86-2.72 (m, 2H), 2.71-2.60(m, 3H), 2.59-2.52 (m, 1H), 2.52-2.43 (m, 1H), 2.31 (d, J=7.3 Hz, 2H),2.21-1.80 (m, 7H), 1.76 (s, 3H), 1.73-1.08 (m, 16H), 1.22 (s, 3H), 1.11(s, 3H), 1.05 (s, 3H), 0.99 (d, J=6.4 Hz, 6H), 0.97 (s, 3H), 0.97 (s,3H).

Example B60 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((2-(4-propionylpiperazin-1-yl)ethyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound (5.5 mg) was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above using propionic acidas the acylating agent. LCMS: m/e 698.8 (M+H)⁺, 3.39 min (method 14). ¹HNMR (500 MHz, DMSO-d₆) δ 7.87 (d, J=8.2 Hz, 2H), 7.22 (d, J=7.9 Hz, 2H),5.25 (d, J=4.9 Hz, 1H), 4.70 (s, 1H), 4.56 (s, 1H), 3.52-3.43 (m, 4H),3.11 (br. s., 2H), 2.71-2.53 (m, 2H), 2.47-2.20 (m, 7H), 2.08 (dd,J=17.2, 6.3 Hz, 1H), 1.97-1.80 (m, 3H), 1.79-1.03 (m, 18H), 1.67 (s,3H), 1.08 (s, 3H), 0.99 (t, J=8.0 Hz, 3H), 0.97 (s, 3H), 0.96 (s, 3H),0.90 (s, 3H), 0.90 (s, 3H).

Example B61 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-butyrylpiperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound (1.2 mg) was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above using butyric acid asthe acylating agent. LCMS: m/e 712.8 (M+H)⁺, 4.97 min (method 15). ¹HNMR (500 MHz, METHANOL-d₄) δ 7.89 (d, J=8.2 Hz, 2H), 7.16 (d, J=8.2 Hz,2H), 5.30 (d, J=4.6 Hz, 1H), 4.78 (s, 1H), 4.68 (s, 1H), 3.79-3.55 (m,4H), 3.12-2.98 (m, 1H), 2.97-2.82 (m, 2H), 2.78 (td, J=10.9, 5.0 Hz,1H), 2.71-2.61 (m, 3H), 2.60-2.54 (m, 1H), 2.52-2.44 (m, 1H), 2.40 (t,J=7.5 Hz, 2H), 2.19-1.80 (m, 6H), 1.75 (s, 3H), 1.73-1.04 (m, 18H), 1.23(s, 3H), 1.11 (s, 3H), 1.05 (s, 3H), 0.99 (t, J=7.5 Hz, 3H), 0.97 (s,3H), 0.97 (s, 3H).

Example B62 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(cyclopropanecarbonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound (0.9 mg) was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above usingcyclopropanecarboxylic acid as the acylating agent. LCMS: m/e 710.8(M+H)⁺, 4.41 min (method 15). ¹H NMR (500 MHz, METHANOL-d₄) δ 7.88 (d,J=7.9 Hz, 2H), 7.16 (d, J=7.9 Hz, 2H), 5.30 (d, J=4.9 Hz, 1H), 4.78 (s,1H), 4.67 (s, 1H), 3.84 (br. s., 2H), 3.77-3.50 (m, 2H), 3.09-2.97 (m,1H), 2.94-2.81 (m, 2H), 2.77 (td, J=10.5, 5.3 Hz, 1H), 2.73-2.57 (m,4H), 2.48 (br. s., 1H), 2.21-1.82 (m, 8H), 1.75 (s, 3H), 1.73-1.07 (m,15H), 1.24 (s, 3H), 1.10 (s, 3H), 1.06 (s, 3H), 0.97 (s, 3H), 0.97 (s,3H), 0.93-0.87 (m, 2H), 0.87-0.79 (m, 2H).

Example B63 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(1-methylcyclopropanecarbonyl)piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound (0.9 mg) was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above using1-methylcyclopropane-1-carboxylic acid as the acylating agent. LCMS: m/e724.8 (M+H)⁺, 4.49 min (method 15). ¹H NMR (500 MHz, METHANOL-d₄) δ 7.89(d, J=8.2 Hz, 2H), 7.16 (d, J=8.2 Hz, 2H), 5.30 (d, J=4.6 Hz, 1H), 4.78(s, 1H), 4.67 (s, 1H), 3.90-3.63 (m, 4H), 3.09-2.98 (m, 1H), 2.96-2.82(m, 2H), 2.81-2.73 (m, 1H), 2.71-2.61 (m, 3H), 2.54 (br. s., 2H),2.24-2.12 (m, 1H), 2.11-1.82 (m, 5H), 1.75 (s, 3H), 1.72-1.14 (m, 16H),1.32 (s., 3H), 1.23 (s., 3H), 1.11 (s, 3H), 1.06 (s, 3H), 0.97 (s, 3H),0.97 (s, 3H), 0.93-0.88 (m, 2H), 0.68-0.58 (m, 2H).

Example B64 Preparation of4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-isobutyrylpiperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoicacid

The title compound (0.4 mg) was prepared from methyl4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoatefollowing the general procedure as described above using isobutyric acidas the acylating agent. LCMS: m/e 712.8 (M+H)⁺, 4.46 min (method 15). ¹HNMR (500 MHz, METHANOL-d₄) δ 7.88 (d, J=8.2 Hz, 2H), 7.15 (d, J=7.9 Hz,2H), 5.30 (d, J=4.9 Hz, 1H), 4.78 (s, 1H), 4.67 (s, 1H), 3.77-3.54 (m,4H), 2.97 (dt, J=13.4, 6.6 Hz, 2H), 2.86-2.71 (m, 3H), 2.70-2.51 (m,4H), 2.46 (br. s., 1H), 2.15 (dd, J=17.1, 6.4 Hz, 1H), 2.08-1.82 (m,5H), 1.75 (s, 3H), 1.73-1.18 (m, 16H), 1.22 (s, 3H), 1.11 (d, J=6.7 Hz,6H), 1.10 (s, 3H), 1.05 (s, 3H), 0.97 (s., 3H), 0.97 (s., 3H),

Example B65 Preparation of(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yltrifluoromethanesulfonate

Step 1. Preparation of(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-ol

To a suspension of betulinic acid (10 g, 21.90 mmol) in 1,4-Dioxane (100mL) was added triethylamine (9.16 mL, 65.7 mmol) and diphenylphosphorazidate (7.08 mL, 32.8 mmol). The mixture was heated to reflux.Upon heating, all solids dissolved. After heating the mixture for 26 h,the mixture was cooled to rt and was concentrated under reducedpressure. The residue was diluted with 100 mL of water and was extractedwith dichloromethane (3×100 mL). The combined organic layers were driedwith sodium sulfate. The drying agent was removed by filtration and thefiltrate was concentrated under reduced pressure. The residue waspurified by flash chromatography in silica gel using a 0-15% EtOAc inhexanes gradient and a Thomson 240 g silica gel column. The fractionscontaining the expected product were combined and concentrated underreduced pressure. A second batch of less-pure product was concentratedand was repurified using a Thomson 240 g column and the same gradientThe fractions containing the expected product were combined with thefirst batch to give(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-ol(7.76 g, 17.10 mmol, 78% yield) as a white solid. ¹H NMR (400 MHz,chloroform-d) δ=4.75 (s, 1H), 4.67-4.62 (m, 1H), 3.20 (dt, J=11.3, 5.6Hz, 1H), 2.55 (td, J=10.9, 5.9 Hz, 1H), 2.17-2.03 (m, 1H), 1.92-1.76 (m,5H), 1.69 (s, 3H), 1.06 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H), 0.85 (s,3H), 0.78 (s, 3H), 1.74-0.66 (m, 19H).

Step 2. Preparation of(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-ol,HCl

To a solution of(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-ol(7.76 g, 17.10 mmol) in 1,4-dioxane (100 mL) was added HCl (37%) (21.07mL, 257 mmol). The mixture was heated to 60° C. for 15 h of heating thenwas cooled to rt and was concentrated under reduced pressure. Theresidue was dissolved in dichloromethane and methanol and wasconcentrated two additional times to give(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-ol,HCl (7.75 g, 16.70 mmol, 98% yield) as an off-white foam. The crudeproduct was used in the next step with no purification.

Step 3. Preparation of tert-butyl((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-3a-yl)carbamate

To a solution of(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-ol,HCl (7.76 g, 16.72 mmol) in 1,4-Dioxane (100 mL) was added water (25mL), sodium bicarbonate (4.21 g, 50.2 mmol) and Boc anhydride (5.82 mL,25.08 mmol). The mixture was stirred at rt for 16 h then the mixture wasdiluted with 100 mL of water and was extracted with ethyl acetate (3×100mL). The combined organic layers were washed with brine, dried overmagnesium sulfate, filtered and concentrated under reduced pressure togive tert-butyl((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-3a-yl)carbamateas an off-white foam. ¹H NMR (500 MHz, chloroform-d) δ=4.74 (d, J=1.6Hz, 1H), 4.64-4.62 (m, 1H), 4.34 (br. s., 1H), 3.24-3.18 (m, 1H),2.63-2.35 (m, 3H), 2.06-1.93 (m, 1H), 1.71 (s, 3H), 1.46 (s, 9H), 1.04(s, 3H), 0.99 (s, 3H), 0.98 (s, 3H), 0.86 (s, 3H), 0.79 (s, 3H),1.77-0.68 (m, 22H).

Step 4. Preparation of tert-butyl((1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-3a-yl)carbamate

To a solution of the resulting tert-butyl((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-3a-yl)carbamatein dichloromethane (100 mL) was added pyridinium chlorochromate (4.69 g,21.74 mmol). The mixture was stirred at rt for 5 h then an additional1.0 g of PCC was added and the mixture was stirred at rt for 1 h. Themixture was filtered through a plug of silica gel and celite which waswashed with a solution of 25% ethyl acetate in hexanes. The filtrate wasconcentrated under reduced pressure to give tert-butyl((1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-3a-yl)carbamateas a light-yellow foam. ¹H NMR (500 MHz, CHLOROFORM-d) δ=4.74 (d, J=1.7Hz, 1H), 4.63 (t, J=1.7 Hz, 1H), 4.34 (br. s., 1H), 2.65-2.34 (m, 5H),2.05-1.88 (m, 2H), 1.71 (s, 3H), 1.47 (s, 9H), 1.10 (s, 3H), 1.08 (s,3H), 1.05 (s, 3H), 0.99 (s, 3H), 0.96 (s, 3H), 1.76-0.93 (m, 18H).

Step 5. Preparation of(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((tert-butoxycarbonyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yltrifluoromethanesulfonate

A solution of the resulting tert-butyl((1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-3a-yl)carbamatein THF (100 mL) was cooled to −78° C. To the solution was added KHMDS(0.91M in THF) (40.4 mL, 36.8 mmol). The mixture was stirred for 20minutes at −78° C. then a solution of1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl)sulfonyl methanesulfonamide(7.47 g, 20.90 mmol) in THF (100 mL) was added via canula. The mixturewas stirred at −78° C. for 5 h then was quenched with 100 mL of waterand was extracted with ethyl acetate (3×75 mL). The combined organiclayers were dried with magnesium sulfate. The drying agent was removedby filtration and the filtrate was concentrated under reduced pressure.The residue was taken up in a small amount of DCM and methanol and theyellow solids that formed were removed by filtration. The filtrate wasagain concentrated and treated with methanol and the solids that formedwere again removed by filtration. The filtrate was concentrated and wasadsorbed to silica gel and was then purified by flash chromatographyusing a 0-50% ethyl acetate in hexanes gradient and a Thomson 240 gsilica gel column. The fractions containing the deprotected product werecombined and were concentrated under reduced pressure to give a mixtureof products The expected product was repurified by flash chromatographyusing a 0-10% EtOAc in hexanes gradient and a 240 g Thomson silica gelcolumn. The fractions containing the expected product were combined andwere concentrated under reduced pressure to give(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((tert-butoxycarbonyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yltrifluoromethanesulfonate (1.31 g, 1.99 mmol, 11.9% over 3 steps). ¹HNMR (500 MHz, CHLOROFORM-d) δ=5.57 (dd, J=6.7, 1.8 Hz, 1H), 4.73 (s,1H), 4.62 (s, 1H), 4.32 (br. s., 1H), 2.64-2.31 (m, 3H), 2.16 (dd,J=17.0, 6.8 Hz, 1H), 2.04-1.94 (m, 1H), 1.70 (s, 3H), 1.45 (s, 9H), 1.13(s, 3H), 1.06 (s, 3H), 1.03 (s, 3H), 0.97 (s, 3H), 0.93 (s, 3H),1.82-0.86 (m, 18H).

Step 6. Preparation of(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yltrifluoromethanesulfonate

To a solution of(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((tert-butoxycarbonyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yltrifluoromethanesulfonate (0.2 g, 0.304 mmol) in dichloromethane (2 mL)was added trifluoroacetic acid (0.5 mL, 6.49 mmol). The mixture wasstirred at rt for 1.5 h then was concentrated under reduced pressure.The residue was diluted with saturated aqueous sodium bicarbonate (20mL) and was extracted with dichloromethane (3×20 mL). The combinedorganic layers were dried with Na₂SO₄. The drying agent was removed byfiltration and the filtrate was concentrated and adsorbed to silica gelthen was purified by flash chromatography using a 12-100% ethyl acetatein hexanes gradient and a 12 g Thomson silica gel column. The fractionscontaining the expected product were combined and were concentratedunder reduced pressure to give(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yltrifluoromethanesulfonate (0.109 g, 0.195 mmol, 64.3% yield) as anoff-white solid. ¹H NMR (500 MHz, chloroform-d) δ=5.57 (dd, J=6.8, 1.9Hz, 1H), 4.73 (d, J=1.6 Hz, 1H), 4.63-4.60 (m, 1H), 2.54 (td, J=10.9,5.3 Hz, 1H), 2.17 (dd, J=17.1, 6.9 Hz, 1H), 2.08-1.99 (m, 1H), 1.70 (s,3H), 1.13 (s, 3H), 1.08 (s, 3H), 1.03 (s, 3H), 0.97 (s, 3H), 0.93 (s,3H), 1.82-0.91 (m, 20H).

Biology Data for the Examples

“μM” means micromolar;

“mL” means milliliter;

“μl” means microliter;

“mg” means milligram;

“μg” means microgram;

The materials and experimental procedures used to obtain the resultsreported in Tables 1-2 are described below.

HIV Cell Culture Assay—

MT-2 cells and 293T cells were obtained from the NIH AIDS Research andReference Reagent Program. MT-2 cells were propagated in RPMI 1640 mediasupplemented with 10% heat inactivated fetal bovine serum, 100 μg/mlpenicillin G and up to 100 units/ml streptomycin. The 293T cells werepropagated in DMEM media supplemented with 10% heat inactivated fetalbovine serum (FBS), 100 units/ml penicillin G and 100 μg/mlstreptomycin. The proviral DNA clone of NL₄₋₃ was obtained from the NIHAIDS Research and Reference Reagent Program. A recombinant NL₄₋₃ virus,in which a section of the nef gene from NL4-3 was replaced with theRenilla luciferase gene, was used as a reference virus. In addition,residue Gag P373 was converted to P373S. Briefly, the recombinant viruswas prepared by transfection of the altered proviral clone of NL₄₋₃.Transfections were performed in 293T cells using LipofectAMINE PLUS fromInvitrogen (Carlsbad, Calif.), according to manufacturer's instruction.The virus was titered in MT-2 cells using luciferase enzyme activity asa marker. Luciferase was quantitated using the Dual Luciferase kit fromPromega (Madison, Wis.), with modifications to the manufacturer'sprotocol. The diluted Passive Lysis solution was pre-mixed with there-suspended Luciferase Assay Reagent and the re-suspended Stop & GloSubstrate (2:1:1 ratio). Fifty (50) μL of the mixture was added to eachaspirated well on assay plates and luciferase activity was measuredimmediately on a Wallac TriLux (Perkin-Elmer). Antiviral activities ofinhibitors toward the recombinant virus were quantified by measuringluciferase activity in cells infected for 4-5 days with NLRlucrecombinants in the presence serial dilutions of the inhibitor. The EC₅₀data for the compounds is shown in Table 2. Table 1 is the key for thedata in Table 2.

Results

TABLE 1 Biological Data Key for EC₅₀ Compounds with EC₅₀ >0.1 μMCompounds with EC₅₀ <0.1 μM Group “B” Group “A”

TABLE 2 Ex- am- ple EC₅₀ # Structure (μM)  1

A  2

A  3

0.004  4

B  5

A  6

A  7

A  8

A  9

0.003  10

A  11

A  12

A  13

A  14

A  15

A  16

A  17

A  18

0.25   19

A  20

0.4   21

A  22

A  23

A  24

A  25

A  26

A  27

A  28

0.004  29

0.01   30

A  31

A  32

0.01   33

A  34

0.002  35

A  36

A  37

0.004  38

A  39

A  40

A  41

A  42

A  43

0.03   44

A  45

A  46

A  47

A  48

A  49

A  50

A  51

A  52

A  53

A  54

A  55

A  56

A  57

A  58

A  59

A  60

A  61

A  62 A  63

A  64

A  65

A  66

A  67

A  68

A  69

A 69-1

A  70

A  71

A  72

A  73

A  74

A  75

A  76

A  77

A  78

A  79

A  80

0.11   81

A  82

A  83

A  84

A  85

A  86

A  87

A  88

A  89

A  90

0.02   91

A  92

A  93

A  94

A  95

A  96

A  97

A  98

A  99

A 100

A 101

A 102

A 103

A 104

A 105

A 106

A 107

A 108

A 109

A 110

A 111

A 112

A 113

A 114

A 115

A 116

A 117

A 118

A 119

A 120

A 121

A 122

A 123

A 124

A 125

A 126

A 127

A 128

A 129

A 130

A 130-1

B 130-2

A 130-3

A 131

A 132

A 133

0.03  134

0.10  135

A 136

A 137

A 138

A 139

A 140

0.009 141

A 142

A 143

A 144

A 145

A 146

A 147

A 148

A 149

A 150

A 151

A 152

A 153

B 154

A 155

A 156

0.12  157

A 158

A 159

A 160

A 161

A 162

A 163

A 164

A 165

A 166

A 167

0.004 168

A 169

A 170

A 171

A 172

A 173

A 174

0.3  175

0.01  176

A 177

0.009 178

A 179

A 180

A 181

A 182

B 183

A 184A

0.39  184B

A 185

B 186

B 187

A 188

0.001 189

A 190

A 191

A 192

A 193

0.02  194

A 195

A 196

A 197

A 198

A 199

A 200

A 201

A A1

A A2

A A3

A A4

A A5

A A6

A A7

A A8

A B1

A B2

A B3

A B4

A B5

A B6

A B7A

A B7B

A B8

A B9

0.01  B10

A B11

A B12

A B13

A B14

A B15

A B16

A B17

A B18

A B19

A B20

A B21

A B22

A B23

A B24

A B25 + A B26

A B27

A B28

A B29

A B30

A B31

A B32

A B33

0.005 B34

A B35

A B36

A B37

A B38

A B39

A B40

A B41

A B42

A B43

A B44

A B45

0.004 B46

A B47

A B48

A B49

A B50

A B51

A B52

A B53

A B54

A B55

A B56

A B57

A B58

A B59

A B60

A B61

A B62

A B63

A B64

A

The foregoing description is merely illustrative and should not beunderstood to limit the scope or underlying principles of the inventionin any way. Indeed, various modifications of the invention, in additionto those shown and described herein, will become apparent to thoseskilled in the art from the following examples and the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims.

What is claimed is:
 1. A pharmaceutical composition which comprises anHIV ameliorating amount of one or more of the compounds which areselected from the group consisting of: a compound of formula I

a compound of formula II

and a compound of formula III

wherein R₁ is isopropenyl or isopropyl; J and E are independently —H or—CH₃, and E is absent when the double bond is present; X is a phenyl orheteroaryl ring substituted with A, wherein A is at least one memberselected from the group of —H, -halo, -hydroxyl, —C₁₋₆ alkyl, —C₁₋₆alkoxy, and —COOR₂; R₂ is —H, —C₁₋₆ alkyl, -alkyl substituted C₁₋₆ alkylor -aryl substituted C₁₋₆ alkyl; Y is selected from the group of —COOR₂,—C(O)NR₂SO₂R₃, —C(O)NHSO₂NR₂R₂, —NR₂SO₂R₂, —SO₂NR₂R₂, —C₃₋₆cycloalkyl-COOR₂, —C₂₋₆ alkenyl-COOR₂, —C₂₋₆ alkynyl-COOR₂,—C₁₋₆alkyl-COOR₂, —NHC(O)(CH₂)_(n)—COOR₂, —SO₂NR₂C(O)R₂, -tetrazole, and—CONHOH, wherein n=1-6; R₃ is —C₁₋₆ alkyl or -alkyl substituted C₁₋₆alkyl; R₄ is selected from the group of —H, —C₁₋₆ alkyl,—C₁₋₆alkyl-C(OR₃)₂—C₃₋₆cycloalkyl, —C₁₋₆ substituted alkyl,—C₁₋₆alkyl-C₃₋₆cycloalkyl, —C₁₋₆ alkyl-Q₁, —C₁₋₆ alkyl-C₃₋₆cycloalkyl-Q₁, aryl, heteroaryl, substituted heteroaryl, —COR₆, —COCOR₆,—SO₂R₂, —SO₂NR₂R₂,

wherein Q₁ is selected from the group of heteroaryl, substitutedheteroaryl, halogen, —CF₃, —OR₂, —COOR₂, —NR₈R₉, —CONR₁₀R₁₁ and —SO₂R₇;R₅ is selected from the group of —H, —C₁₋₆ alkyl, —C₃₋₆ cycloalkyl,—C₁₋₆ alkyl substituted alkyl, —C₁₋₆alkyl-NR₈R₉, —COR₁₀, —COR₆, —COCOR₆,—SO₂R₂ and —SO₂NR₂R₂; with the proviso that only one of R₄ or R₅ can beselected from the group of —COR₆, —COCOR₆, —SO₂R₇ and —SO₂NR₂R₂; or R₄and R₅ are taken together with the adjacent N to form

R₆ is selected from the group of —H, —C₁₋₆ alkyl, —C₁₋₆alkyl-substituted alkyl, —C₃₋₆ cycloalkyl, —C₃₋₆ substitutedcycloalkyl-Q₂, —C₁₋₆ alkyl-Q₂, —C₁₋₆ alkyl-substituted alkyl-Q₂, —C₃₋₆cycloalkyl-Q₂, aryl-Q₂, —NR₁₃R₁₄, and —OR₁₅; wherein Q₂ is selected fromthe group of aryl, heteroaryl, substituted heteroaryl, —OR₂, —COOR₂,—NR₈R₉, SO₂R₂, —CONHSO₂R₃, and —CONHSO₂NR₂R₂; R₇ is selected from thegroup of —C₁₋₆ alkyl, —C₁₋₆ substituted alkyl, —C₃₋₆cycloalkyl, aryl,and heteroaryl; R₈ and R₉ are independently selected from the group of—H, —C₁₋₆ alkyl, —C₁₋₆ substituted alkyl, aryl, heteroaryl, substitutedaryl, substituted heteroaryl, —C₁₋₆ alkyl-Q₂, and —COOR₃, or R₈ and R₉are independently selected from the group of

or R₈ and R₉ are taken together with the adjacent N to form a cycleselected from the group of:

with the proviso that only one of R₈ or R₉ is —COOR₃; R₁₀ and R₁₁ areindependently selected from the group of —H, alkyl, —C₁₋₆ substitutedalkyl and —C₃₋₆ cycloalkyl, or R₁₀ and R₁₁ are taken together with theadjacent N to form the cycle

R₁₂ is selected from the group of —C₁₋₆ alkyl, —NR₂R₂, —C₁₋₆ alkyl-OH,—C₁₋₆ alkyl, —C₁₋₆ substituted alkyl, —C₃₋₆ cycloalkyl, —COR₇,—COONR₂₂R₂₃, —SOR₇, and —SONR₂₄R₂₅; R₁₃ and R₁₄ are independentlyselected from the group of —H, —C₁₋₆ alkyl, —C₃₋₆ cycloalkyl, —C₁₋₆substituted alkyl, —C₁₋₆ alkyl-Q₃, alkyl-C₃₋₆ cycloalkyl-Q₃, C₁₋₆substituted alkyl-Q₃ and

or R₁₃ and R₁₄ are taken together with the adjacent N to form a cycleselected from the group of:

Q₃ is selected from the group of heteroaryl, substituted heteroaryl,—NR₂₀R₂₁, —CONR₂R₂, —COOR₂, —OR₂, and —SO₂R₃; R₁₅ is selected from thegroup of —C₁₋₆ alkyl, —C₃₋₆ cycloalkyl, —C₁₋₆ substituted alkyl, —C₁₋₆alkyl-Q₃, —C₁₋₆ alkyl-C₃₋₆ cycloalkyl-Q₃ and —C₁₋₆ substituted alkyl-Q₃;R₁₆ is selected from the group of —H, —C₁₋₆ alkyl, —NR₂R₂, and —COOR₃;R₁₇ is selected from the group of —H, —C₁₋₆ alkyl, —COOR₃, and aryl; R₁₈is selected from the group of —COOR₂ and —C₁₋₆ alkyl-COOR₂; R₁₉ isselected from the group of —H, —C₁₋₆ alkyl, —C₁₋₆ alkyl-Q₄, —COR₃,—COOR₃, wherein Q₄ is selected from the group of —NR₂R₂ and —OR₂; R₂₀and R₂₁ are independently selected from the group of —H, —C₁₋₆ alkyl,—C₁₋₆ substituted alkyl, —C₁₋₆ substituted alkyl-OR₂, and —COR₃, or R₂₀and R₂₁ are taken together with the adjacent N to form a cycle selectedfrom the group of

with the proviso that only one of R₂₀ or R₂₁ can be —COR₃, R₂₂ and R₂₃are independently selected from the group of H, —C₁₋₆ alkyl, —C₁₋₆substituted alkyl, and —C₁₋₆cycloalkyl, or R₂₂ and R₂₃ are takentogether with the adjacent N to form a cycle selected from the group of

R₂₄ and R₂₅ are independently from the group of H, —C₁₋₆ alkyl, —C₁₋₆substituted alkyl, —C₁₋₆ alkyl-Q₅, —C₁₋₆cycloalkyl, aryl, substitutedaryl, heteroaryl, and substituted heteroaryl, and Q₅ is selected fromthe group of halogen and SO₂R₃; including pharmaceutically acceptablesalts thereof; together with one or more pharmaceutically acceptablecarriers, excipients or diluents.
 2. The pharmaceutical composition ofclaim 1, useful for ameliorating infection by HIV, which additionallycomprises an HIV ameliorating amount of an AIDS treatment agent selectedfrom the group consisting of: (a) an AIDS antiviral agent; (b) ananti-infective agent; (c) an immunomodulator; and (d) another HIV entryinhibitor.